antibiotics
Review
Ethnopharmacology, Antimicrobial Potency, and
Phytochemistry of African Combretum and Pteleopsis Species
(Combretaceae): A Review
Heidi Silén, Enass Y. A. Salih, Eunice Ego Mgbeahuruike and Pia Fyhrqvist *
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
* Correspondence: pia.fyhrquist@helsinki.fi
Citation: Silén, H.; Salih, E.Y.A.;
Mgbeahuruike, E.E.; Fyhrqvist, P.
Ethnopharmacology, Antimicrobial
Potency, and Phytochemistry of
Abstract: Bacterial and fungal resistance to antibiotics is of growing global concern. Plants such as
the African Combretum and Pteleopsis species, which are used in traditional medicine for the treatment
of infections, could be good sources for antimicrobial extracts, drug scaffolds, and/or antibiotic
adjuvants. In African countries, plant species are often used in combinations as traditional remedies.
It is suggested that the plant species enhance the effects of each other in these combination treatments.
Thus, the multi-species-containing herbal medications could have a good antimicrobial potency.
In addition, plant extracts and compounds are known to potentiate the effects of antibiotics. The
objective of this review is to compile the information on the botany, ethnopharmacology, ethnobotany,
and appearance in herbal markets of African species of the genera Combretum and Pteleopsis. With
this ethnobotanical information as a background, this review summarizes the information on the
phytochemistry and antimicrobial potency of the extracts and their active compounds, as well as
their combination effects with conventional antibiotics. The databases used for the literature search
were Scopus, Elsevier, EBSCOhost, PubMed, Google Scholar, and SciFinder. In summary, a number
of Combretum and Pteleopsis species were reported to display significant in vitro antibacterial and
antifungal efficacy. Tannins, terpenes, flavonoids, stilbenes, and alkaloids—some of them with good
antimicrobial potential—are known from species of the genera Combretum and Pteleopsis. Among
the most potent antimicrobial compounds are arjunglucoside I (MIC 1.9 µg/mL) and imberbic acid
(MIC 1.56 µg/mL), found in both genera and in some Combretum species, respectively. The in vitro
antimicrobial properties of the extracts and compounds of many Combretum and Pteleopsis species
support their traditional medicinal uses.
African Combretum and Pteleopsis
Species (Combretaceae): A Review.
Keywords: Combretum; Pteleopsis; antibacterial; antifungal; traditional medicine; antibiotic adjuvants
Antibiotics 2023, 12, 264.
https://doi.org/10.3390/
antibiotics12020264
Academic Editor: Marcello Iriti
Received: 15 December 2022
Revised: 19 January 2023
Accepted: 20 January 2023
Published: 28 January 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1. Introduction
Bacterial and fungal resistance to antibiotics is of growing global concern [1]. Drugresistant tuberculosis (TB), the number one infectious-disease killer globally, causes 1.8 million deaths per year, and there are only a limited number of successful second-line
treatments against multi-drug-resistant- (MDR-TB) and extensively-drug-resistant- (XDRTB) tuberculosis [2]. Other important, antibiotic-resistant bacteria include methicillinresistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and
carbapenem-resistant Enterobacteriaceae (CRE) [1]. In addition, the incidence of antibiotic resistance is increasing among bacteria, causing serious diarrhea and sepsis, such as
with Clostridioides difficile, Escherichia coli, and Klebsiella pneumoniae [3,4]. Candida glabrata
has demonstrated an increased significance among the human-pathogenic isolates of the
Candida species, and many clinical isolates of C. glabrata are reported to be more resistant
to amphotericin-B than C. albicans [5]. In their report on new, approved antibiotics in the
drug pipeline, the WHO [3] noted that most of these antibiotics are derivatives of known
classes, and therefore a fast development of emerging resistance against these agents is
foreseen. There is a need for new antibiotic treatments, including combination therapies,
Antibiotics 2023, 12, 264. https://doi.org/10.3390/antibiotics12020264
https://www.mdpi.com/journal/antibiotics
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to combat resistant bacteria and fungi. Higher plants used in traditional medicine for
the treatment of bacterial and fungal infections could be potential sources of antibiotic
potentiators (adjuvants) and new antibiotic scaffolds [6,7].
This review focuses on the African species of the genera Combretum and Pteleopsis,
which could play an important role in the development of new antibiotic scaffolds and/or
antibiotic adjuvants. In Africa, plants from various regions have been used as medicine
since ancient times, including for the treatment of infections and their symptoms [8].
Depending on the country and the region (countryside or city), approximately 60–80% of
the people in Africa utilize plants as their primary form of medical treatment [9]. Although
a number of extracts and compounds from African medicinal plants have been reported to
possess promising antimicrobial potential, either alone or as antibiotic adjuvants, only a
small proportion of the drugs derived from these plants have been marketed globally, and
none of these drugs are antimicrobials [10]. Instead, extracts and compounds are utilized
commercially as antioxidants and skin creams, among other uses [11].
This review compiles the botany, ethnopharmacology, and antimicrobial potential
of some African species of the genera Combretum and Pteleopsis, both belonging to the
pantropical Combretaceae family [12–18]. A study which aimed to reveal plant taxa with
antimicrobial properties confirmed that the family Combretaceae demonstrated the largest
relative number of genera and species with antimicrobial properties [12], Figure 1. This
result encourages further studies on the antimicrobial potential of plant species belonging
to this family. In Africa, many traditional medicinal uses of Combretum and Pteleopsis species
are related to the treatment of infections and their symptoms [13,19–21]. Moreover, there
are several herbal formulations of plant extracts from the Pteleopsis and Combretum species,
in both African and international markets, that are briefly discussed in this review [20].
11
6
Combretaceae
5
Cupressaceae
Lauraceae
10
42
Zingiberaceae
Meliaceae
10
Myrtaceae
Lamiaceae
11
14
Fabaceae
Others
Figure 1. The significant role of plants of the family Combretaceae among antibacterial plants of the
world. The percentages indicate the percent of genera with antibacterial properties within a plant
family. Modified from Prasad et al. [12].
In accordance with their traditional uses for the treatment of infection, numerous
in vitro studies have confirmed that African Combretum species possess antibacterial and
antifungal properties [22,23]. Species of the genus Pteleopsis have been studied to a lesser
extent, although there are reports confirming the antimicrobial activities of P. myrtifolia
and P. suberosa [24,25]. Most of the studies report on the activities of extracts and, in some
cases, active compounds have been isolated. Antimicrobial compounds in Combretum and
Pteleopsis species include ellagitannins, ellagic acid derivatives, gallotannins, terpenoids,
saponins, fatty acids, fatty alcohols, flavonoids, stilbenoids, lignans, non-protein amino
acids, and alkaloids [26–28]. In this review paper, the antimicrobial effects of extracts from
various parts and with various polarities from African Combretum and Pteleopsis spp. are
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summarized. In addition, a number of secondary metabolites isolated from the genera are
discussed in relation to their antimicrobial activities.
Studies have shown that extracts and compounds from some species of Combretum
have strong synergistic and/or additive effects when used with conventional antimicrobial
agents and with other plant extracts [19,29–31]. In this context, it is important to note that
there are no combination or synergistic studies on Pteleopsis species. The concept of using
plant-derived extracts and compounds to increase and preserve the effects of conventional
antibiotics is important when combating resistant bacteria and fungi. However, this aspect
has not been studied enough with respect to the antibiotic adjuvant potential of extracts
and compounds from the Combretum and Pteleopsis species. Altogether, this review presents
some Combretum species that should be focused on in more detail regarding their potential
as producers of antibiotic adjuvants.
Although a number of ethnopharmacological studies have been performed on Combretum and Pteleopsis species, there is still a vast amount of undocumented information;
most of the knowledge on the traditional medicinal uses of these plants is passed down
orally [32]. The loss of forests and other habitats, as well as the movement of young people
to cities in Africa, has also accelerated the loss of information concerning medicinal plants in
general [32]. Therefore, this review aims to compile the documented ethnopharmacological
information in order to facilitate future ethnopharmacological research on species that have
not been studied much in this respect. Moreover, extracts and compounds with confirmed
antibacterial and/or antifungal activities—either alone or in combination studies with
conventional antibiotics—are presented (preferably in relation to the ethnopharmacological
use of the plant, if this information is available). The genera and species presented in this
review contain valuable scaffold molecules for new antibiotics and/or antibiotic adjuvants.
This review will serve as a reference guide and will provide insight for further studies that
aim to find (new) antimicrobials and antibiotic adjuvants. It will also guide studies that
aim to find antimicrobial extracts from the African Combretum and Pteleopsis species, both
with respect to follow-up studies and to encourage the study of as-yet-unexplored species.
2. Methodology
The data sources used in the literature search were the Scopus, Elsevier, EBSCOhost,
PubMed, Google Scholar, African Plant Database, The Plant List Database, and SciFinder
electronic databases. The search phrases used included “ethnopharmacology and antibacterial activity of Pteleopsis species”, “ethnopharmacology and antibacterial activity of Combretum species”, “antifungal activity of Pteleopsis species”, “antifungal activity of Combretum
species”, “phytochemistry of Pteleopsis species”, “phytochemistry of Combretum species”,
“Combretum species and infections”, “Combretum species and traditional medicine”, “Pteleopsis species and infections”, and “Pteleopsis species and traditional medicine”. Articles
published between 1962 and 2022 were considered in the review. The older references were
especially important regarding the ethnobotanical uses of the Combretum and Pteleopsis spp.
in Africa. Many articles were accessed, and some inclusion and exclusion criteria were
applied to include only the relevant articles. The CAS SciFindern 2022 and CAS registry
number databases were used to identify and authenticate the detected chemical structures
in the Combretum and Pteleopsis spp. ChemDraw® software was used to draw the molecular
structures in this review paper.
3. Botany, Ethnopharmacology, and Importance in Herbal Markets of African
Combretum and Pteleopsis Species
3.1. The Genus Combretum
3.1.1. Botany
Approximately 140 Combretum species occur in tropical Africa, including deciduous
or semi-deciduous trees and shrubs as well as woody climbers and, in some rare cases,
subshrubs with woody rootstocks (Figure 2) [16,33]. The flowers are inconspicuous or
showy, with red, pink, yellow–green, yellow, or cream–white petals. The fruits, numbering
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between four and five, are winged with a thin, papery pericarp. The base of the leaf
petioles may persist as spines, such as in C. constrictum (Figure 2B). The morphology of the
fruit is considered useful for species identification. Moreover, the trichomes—glandular
hairs on the leaves— have been found to be useful for the classification of Combretum
species in combination with other taxonomical characters [16]. However, despite extensive
anatomical and taxonomic research, the taxonomy and nomenclature within the genus
Combretum is still unclear [16]. A large number of Combretum spp. occur in deciduous,
savanna woodland habitats (such as the Miombo woodlands in East Africa) and wooded
grasslands. Additionally, some species occur in rainforest habitats [34,35].
Figure 2. Combretum species in Africa. (A) Combretum hereroense in savanna woodland;
(B) Combretum constrictum in riverine forest vegetation; (C) fruiting branch of Combretum zeyheri;
and (D) Combretum orchard in Tanzania with C. molle. Photos: Pia Fyhrqvist.
3.1.2. Ethnopharmacology
At least twenty-four (24) species of Combretum are well-known in traditional African
medicine, with a diverse range of uses that include remedies for snake and scorpion bites,
worms, malaria, and topical and internal bacterial and fungal infections [36]. Sixteen of
these Combretum species are discussed in this review. A number of Combretum species
are traded in herbal markets in Limpopo, South Africa, Tanzania, and the Republic of
Benin [37]. Moreover, some Combretum species such as C. adenogonium and C. micranthum
are used by African immigrants in New York, U.S.A., and are therefore commonly available
there in herbal medicine markets [38]. Traditional herbal remedies made from Combretum
species include hot-water decoctions, cold-water extracts (macerations), infusions, teas,
tinctures, porridges, and fresh leaf juices [29,36,37,39]. Volatile compounds in the plants
may also be inhaled; for example, as a smoke inhalation of burnt plant material or as
fumes from steam baths or hot water extracts. In addition, dried or fresh plant material
is applied topically for wound care as ointments/dressings. All parts of the Combretum
species—in some cases even the fruits or seeds—are used for medicinal purposes, although
the fruits of some species are thought to be poisonous [40]. Table 1 summarizes some
Combretum species used for the treatment of infectious diseases and their symptoms in
African traditional medicine. The geographical occurrence, main botanical characters, and
traditional medicinal uses of the species of Combretum in Table 1 are explained in more
detail in the next paragraphs.
C. molle (the soft-leaved Combretum, velvet bush willow, and velvet-leaf willow) occurs
in woodlands, open woodlands, rocky areas, and wooded grasslands throughout tropical
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Africa and in the Arabian Peninsula (Figure 2D). It grows into a medium-sized or large tree
(up to 17 m) with a dense crown and rough, reticulate, and fissured bark [41]. The leaves
are oppositely arranged, and the lamina is pubescent above and covered with dense, grey
hairs on its lower surface. The greenish yellow, fragrant flowers are borne in axillary spikes.
The elliptic- to oval-shaped fruit is a four-winged samara fruit with an apical peg [40].
C. molle is widely used in African traditional medicine for fever, colds, wounds, and pain.
Moreover, the plant is used to treat a range of topical and internal infections, including
HIV/AIDS [41]. Roots, leaves, and stem bark are the most commonly used parts, while the
fruits are more seldom used [40]. The inner part of the root is used in wound dressings,
and root decoctions are used for dysentery. The stem bark is used for the treatment of
stomach problems. The leaves are used as anthelminthics and antidiarrheals [40]. In Mali,
decoctions and powders are most commonly used in preparations for the treatment of
dermatitis [42]. In Ethiopia, aqueous extracts of the stem bark are used for tuberculosis [43].
The seeds of this plant are widely used for the treatment of malaria by residents of rural
areas of Ethiopia, mainly in the Gambella regional state [40].
C. molle can be found in herbal medicine markets in Africa. As this species is common
in Africa, it is not on the list of vulnerable or endangered species, unlike many other
medicinal plants. In Limpopo, South Africa, the roots are sold for the treatment of tuberculosis and skin disorders [37]. In Tanzania especially, the roots of C. molle are sold
in marketplaces [44]. C. molle is also traded as an important medicinal plant in the Siby
village in the Dioilan region of Mali, where the most common production methods for
C. molle are decoctions and powders. In Mali, the most commonly used plant parts are
leaves (37.7%), trunk bark (18.6%), whole plant (13.0%), and roots (10.7%) [42]. In addition
to being an important ingredient as a single plant species in traditional medicine, C. molle
is also commonly mixed with other plants: the roots of C. molle are mixed with the roots
of Annona chrysophylla Boj. or Annona senegalensis Pers. to produce mucus-secreting or
expectorant effects to treat coughs. In the treatment of syphilis, the roots of C. molle are
combined with the following species, among others: Securinega virosa Pax et K. Hoffm.
(Euphorbiaceae), Psorospermum febrifugum var. ferrugineum Keay & Milne-Redhead, and
Premna senensis Klotsch (Verbenaceae) [17,36]. In the treatment of snake bites, the roots of
C. molle are combined with the roots of Markhamia obtusifolia Sprague (Bignoniaceae) and
Vangueria rotundata Robyn (Rubiaceae).
C. micranthum occurs in dry, often degraded savanna on stony and gravelly soils,
outcrops, and termite hills, often following streambeds from sea level up to 1000 m altitude.
C. micranthum (kinkéliba, synonym for medicine in some African languages) is an undomesticated shrub species found in the Tiger bush region (the name comes from tiger-patterned
vegetation) of western Africa and in the Sahel region [45]. C. micranthum is a small tree (up
to 10 m), shrub, or woody climber that can reach up to 20 m in height. It has pale grey bark
and orange-to-red stems, with bark that peels in long, fibrous, red–brown strips [45]. Its
leaves, which are hairy on the midrib, are oppositely arranged or are arranged in whorls of
three, with a rounded base, brown scales beneath. The flower receptacle consists of two
parts: the petals, which are free from each other and cream-coloured, and the style, which is
up to 2.5 mm long and ranges from being hairy to almost glabrous. The flowers are typically
rich in nectar and thus attract insects (especially bees), birds, and small mammals [45].
C. micranthum (Kinkéliba, bush tea) has been considered to belong to the fifty (50) most
important medicinal plants in Africa and is inscribed in the French Pharmacopoeia [13,46].
It is used for the treatment of bruises and sprains by rubbing the root powder into shea
butter or palm oil and applying the paste on the skin [45]. The roots are also used in
decoctions as an anthelminthic to treat, e.g., guinea worm (Dracunculus guinensis) infestations, or as a wash in the treatment for open wounds [45]. C. micranthum leaves are
used as an herbal infusion or tea, both of which are recognized to have therapeutic effects
as antibacterial, antiviral, anti-inflammatory, and antimalaria remedies [47]. The most
common use of kinkéliba is as a beverage made from the dried leaves, which is used for
diuretic and digestion purposes, including gastrointestinal problems, colic, and vomiting.
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The dried leaves have been found to have hypoglycemic activity [20,27]. The leaves of
C. micranthum (maceration/decoction/oral/bath) are used as an antimalarial medicine in
malaria-endemic areas of the Ségou region, Mali [48,49]. In Guinea, C. micranthum is used
for the treatment of tuberculosis [45]. In Senegal, Mali, Burkina Faso, and western Africa,
C. micranthum is widely used as a general panacea [13]. The leaves, stem bark, and roots
of C. micranthum are widely sold in local markets for a variety of diseases. In Mali, the
powdered plant parts are sold in the form of tea bags to treat liver problems and diarrhea.
C. imberbe (Leadwood) occurs mainly south of the equator in open woodland and
wooded savanna, growing in a wide variety of soils from sandy soils to limestone outcrops.
It is most commonly found along rivers. C. imberbe is a deciduous shrub or small- to
medium-sized tree (up to 20 m tall). The color of the trunk is pale grey or dark grey, and
the snakeskin-like bark is its main morphological feature. The leathery leaves are arranged
opposite to one another, hairless and grey–green [16]. The sweetly scented flowers are
borne in axillary spikes and are yellowish cream colored [16]. Flowers are produced from
November to March. The fruit is a four-winged samara, yellowish green with silvery scales.
The colour of the mature fruits turn to pale red from February to June. C. imberbe is used
throughout southern Africa as a traditional medicinal plant [50]. The powdered roots or
leaves or their decoctions are used as a treatment for stomach problems and diarrhea, colds,
coughs, and chest pains, all of which are symptoms that can be related to bacterial and
fungal infections [51]. As a remedy for coughs, the smoke of burnt leaves is inhaled or
the leaves are chewed [52]. General STI infections (sexually transmitted infections) are
treated by crushing the leaves, suspending them in water, and drinking the remedy as an
infusion [53–55]. In Namibia (Oshikoto region), C. imberbe infusions are used for two to
seven days to cure gonorrhea [56]. In Zimbabwe, Zambia, Namibia, and Mozambique,
C. imberbe is used for treating malaria, diarrhea, and bilharzia [57,58]. The root infusion
is used for female infertility, and the bark powder is applied externally as a treatment
against leprosy. Its ashes are used in commercially sold toothpaste [52]. The flowers are
used to make a cough medicine that can be bought in local markets. C. imberbe is used
with Sclerocarya birrea subsp. caffra, Diospyros lycioides, Combretum erythrophyllum, and other
species to restore or revive fertility in women.
C. erythrophyllum (river bushwillow, bushwillow, river Combretum) occurs in riverine
forests or savannas with sufficient groundwater in South Africa, Botswana, Mozambique,
Namibia, and Zimbabwe [59]. C. erythrophyllum is a medium to large deciduous tree, growing up to 10–12 m tall, often with multiple stems and a spreading crown with some branches
growing near the ground, thus giving it a willow-like appearance. Additionally, a large
number of upright branches can sprout from the branches growing near the ground [60].
The bark is a greyish brown and flakes with age to expose grey patches. When mature, the
leaves are dark green and shiny, whereas the young leaves are yellowish and shiny. The
leaves turn red in the autumn, hence the name erythrophyllum. The flowers, which grow
on dense axillary spikes, are greenish yellow and lightly scented with a sweet scent. The
four-winged fruit (between 10 and 15 mm in length) changes color from green to yellowbrown when it ripens. The seeds, borne in the winged fruit capsules, are poisonous [61].
C. erythrophyllum is widely used in South African traditional medicine. Root, stem, and
bark decoctions are used to treat leprosy and as a cure for coughs; a decoction is drunk three
to four times per day [60]. Leaf infusions and roots are used to treat abdominal pains, while
the dried, powdered gum is used for wounds [60]. Fresh or powdered leaves and roots
are inserted into the vagina as a cure and prophylactic for venereal diseases [60]. Leaves
are used for coughs, colds, infertility, venereal diseases, diarrhea and dysentery, sores, and
wounds [29]. In Zimbabwe and among the Zulu in South Africa, C. erythrophyllum is used
to treat infertility, for the maintenance of pregnancy (stem bark), and to facilitate birth
(seeds/fruits).
C. aculeatum is native to the Sudano-Sahelian savanna region and the forest–savanna
mosaic regions in Africa. Its geographical occurrence extends in a belt from West to East
Africa. C. aculeatum grows as a scandent shrub or woody climber (between 4.5 and 8 m
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tall) and the leaf petioles become spines when mature. The young branches are pubescent
or pilose. The leaves are lightly pubescent on both sides of the lamina. The flowers are
white and scented. The fruit is indehiscent, obovate, five-winged, and has a shiny, purplish
color when young [62]. C. aculeatum is a popular medicinal plant in the Sudano-Sahelian
area [63]. In Sudan, extracts of the bark, seeds, and leaves are used to treat tuberculosis of
the skin [63]. Additionally, extracts of the leaves are used as laxatives and to treat venereal
diseases, extracts of the stem are used to treat skin infections such as leprosy, and decoctions
of the root are used orally to treat influenza in Sudan [64]. Moreover, in Senegal, water
decoctions of the aerial parts and root are used for TB and catarrh [65,66]. In Ethiopia,
extracts of branches are used to treat eye problems and dysentery [63]. In Senegal, the Serer
treat eye problems with the sap taken from the center of the stem. In Senegal, root powder
is rubbed over the body to treat leprosy [66].
C. adenogonium (syn. C. fragrans, four-leaved bushwillow, four-leaved Combretum)
occurs widely in tropical Africa, from Senegal and Guinea in West Africa to Ethiopia,
Eritrea, Kenya, and Tanzania in East Africa. It is also found in Zimbabwe and Mosambique.
Its common growth habitats are deciduous woodlands and wooded grasslands, often in
association with seasonally waterlogged clay soils. C. adenogonium grows into a small
tree (12–15 m tall) with reticulately fissured, grey bark and red twigs. The leaves are
arranged oppositely or in whorls of three to four and are broadly to narrowly elliptic.
The scented flowers are a greenish yellow, arranged in axillary spikes. The fruit is an
almost-circular to elliptic four-winged nut (Samara fruit) with a yellow–brown to brown
color [67]. C. adenogonium has numerous uses in African traditional medicine. Leprosy,
coughs, diarrhea, and syphilis are treated with root decoctions of this plant [36,65,66].
In addition, leaf decoctions are used to clean wounds and for fungal infections of the
scalp [36,44]. Moreover, decoctions of the stem, root, and leaves are applied to new and
chronic wounds [68].
C. apiculatum (red bushwillow, rooibos—not to be confused with Apalathus linearis)
is native to tropical eastern and southern Africa in woodlands, wooded grasslands, and
Acacia-Commiphora shrublands. It grows into a small, much-branched, deciduous tree (up
to 10 m tall). The leaves are oppositely arranged and shortly petiolate, and the leaf tip is
apiculate. The yellow flowers are without fragrance and arranged in axillary spikes. The
four-winged fruit has a yellowish green to reddish color [67]. Decoctions of the root are
used for the treatment of leprosy and bloody diarrhea [65,69].
Table 1. Species of Combretum and Pteleopsis used in African traditional medicine for the treatment of
infections and their symptoms.
Species Name and Geographical
Occurence
Part of Plant Used and Herbal
Preparation
Traditional Medicinal Uses
References
C. aculeatum Vent.
From West to East Africa via the
Sudano-Sahelian belt
Water decoctions of aerial parts
and roots
Tuberculosis, laxatives, venereal
diseases, leprosy, skin infections, colic,
diarrhea, intestinal disorders, wounds,
gastritis, eye treatments,
stomach troubles
[63–66]
C. adenogonium Steud ex A. Rich.
syn. C. fragrans F. Hoffm
Widely distributed in tropical Africa
from West to East Africa and south
to Zimbabwe and Mozambique
Leaves, barks, and roots are used
as decoctions, infusions
and macerates
Diarrhea, leprosy, syphilitic sores,
coughs, snakebites, wounds, sores,
chest and abdominal pains,
schistosomiasis, and fungal infections
of the scalp
[17,36,44,65–68]
Leaf extracts, leaf decoctions, and
root decoctions
Stomach problems, disinfection of the
navel after birth, venereal diseases,
conjunctivitis, schistosomiasis,
abdominal disorders, leprosy,
and conjunctivitis
[66,69,70]
C. apiculatum Sond.
East, south, and
southwestern Africa
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Table 1. Cont.
Species Name and Geographical
Occurence
Part of Plant Used and Herbal
Preparation
Traditional Medicinal Uses
References
C. collinum Fresen.
Widespread in dry savanna areas in
tropical Africa. Occurs from Senegal
to East Africa and south throughout
southern Africa
Roots, boiled roots, barks, leaves,
gum are used as decoctions; roots
and twigs are chewed
Stomachache, purgative, diuretic,
coughs, toothache, dysentery, snake
bites, colds, chronic diarrhea,
panaritium (nail bed inflammation),
infertility, venereal diseases, sores,
wounds, and malaria
[29,49,53,54,56,69,71]
C. erythrophyllum (Burch.) Sond.
Native to southern
African countries
Root, stem, and bark decoctions;
dried powdered gum and leaves
Coughs, colds, leprosy, wounds and
sores, prophylactic for venereal
diseases, infertility,
diarrhea, and dysentery
[29,35,60,61]
C. hartmannianum Schweinf.
Horn of Africa, Sudan, South Sudan,
Eritrea, Ethiopia
Roots, leaves, stem bark, stem
wood, macerations, decoctions,
tonics, pastes, ointments, and
smoke fumigant
Abdominal pain, sore throat,
dysentery, fever, jaundice, sexually
transmitted diseases, fungal nail
infections, rheumatism, fatigue, skin
diseases, acne, wounds, ulcer
infections, leprosy, and
bacterial infections
[64,72–78]
C. hereroense Shinz
In tropical Africa from Angola in
West Africa to the Sudan in East
Africa, as well as growing on a strip
from Kenya to Zimbabwe
Shrub, leaves, and crushed leaves
are suspended in water and used
as a cold infusion
Roots, leaves, young shoots, and
barks are used as decoctions
Headache, female infertility, gonorrea,
chlamydia symptoms in men, coughs,
stomach problems, chest problems,
schistosomiasis, abdominal ulcers,
wounds, malaria, leprosy,
and toncillitis
[35,51,53,54,69,71,79]
C. imberbe Wawra
Occurs mainly in African countries
south of the equator
Powdered roots, leaves or bark
are used as decoctions; the smoke
of burnt leaves is inhaled; leaves
are chewed; infusions of leaves
and roots are taken orally; and
ashes of the wood are used
as toothpaste
Stomach problems and diarrhea, colds,
coughs and chest pains, sexually
transmitted infections, malaria,
bilharzia, female infertility, leprosy,
viral, bacterial and fungal infections,
and toothpaste
[51–58,80]
C. kraussii Hochst syn. C. nelsonii
Duemmer
Leaf extracts, roots, and leaves
Bacterial respiratory diseases and
wound healing
[22,81–83]
C. micranthum G. Don
West African savanna region
Leaves, seeds, stem bark and
roots are used as dried powders
and decoctions, juice is made
from fresh roots, root powder, and
fruit (dried and fresh), steam
baths, and infusions or tea
Wounds, burns, insect stings, nausea,
coughs, bronchitis, fever, toothache,
malaria, massage, sores, diuretic,
diarrhea, ointment, treatment of
bruises, colds, vomiting, and
gastrointestinal problems
[20,45,47–49,53,54,84,85]
Barks, roots, leaves, infusions,
and twigs
Dental caries and bad smell, wound
dressing, skin disorders, dysentery,
snakebite, coughs, pneumonia, fever,
inhalant for chest complaints,
tuberculosis, leprosy, dysentery,
stomach problems, edema, worms,
gonorrhea, syphilis, venereal diseases,
malaria and HIV, extracts of leaves
inhaled as steam bath, and peeled
twigs as chewing sticks
[13,35–37,40–43,59,69,70,86]
C. nigricans Lepr. ex Guill. et Perr.
Sénégal, Mauretania, Niger,
Burkina Faso
The gum exudated from the bark
and roots
Gastrointestinal disorders, enteralgia
(colic), stomach problems, acne,
jaundice, arthritis, rheumatism,
cataract, conjunctivitis, headaches,
and malaria
[64,80,87,88]
C. padoides Engl. & Diels
Tropical and south-eastern Africa
Leaves, roots, crushed leaves,
decoctions, and water extracts
Snakebites, wounds, hookworms,
malaria, diarrhea, conjuctivitis, and
bacterial and fungal infections
[69,80,88,89]
C. pentagonum M. A. Lawson syn. C.
lasiopetalum Engl. & Diels
South-East Kenya to South
Tropical Africa
Roots, leaves
Wounds, edema, gonorrhea, loose
tooth, and bleeding gums
[71]
C. molle R. Br. ex G. Don
Throughout tropical Africa and the
Arabian Peninsula
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Table 1. Cont.
Species Name and Geographical
Occurence
Part of Plant Used and Herbal
Preparation
Traditional Medicinal Uses
References
C. psidioides Welw
Angola, Namibia, Tanzania,
Zimbabwe
Decoction of roots; fresh,
pounded leaves mixed with
porridge; and in combination
with C. molle and C. zeyheri
Diarrhea, oedema, and back and
muscle pains
[36]
C. zeyheri Sond.
From Kenya to eastern DR Congo
and northern Namibia to
north-eastern South Africa
Barks, roots, leaves, the smoke of
burnt leaves, decoctions,
water extracts
Smallpox, nose bleeding,
hemorrhoids, diarrhea, bloody
diarrhea, coughs, toothaches, bacterial
and fungal infections, scorpion bite,
dry wounds, schistosomiasis, and
eye inflammation
[17,35,51,59,69]
P. hylodendron Mildbr.
West and Central Africa, Cameroon
Decoctions of stem bark, leaf sap
Measles, chickenpox, sexually
transmitted diseases, female sterility,
liver and kidney disorders,
and epilepsy
[90,91]
P. myrtifolia (Laws.) Engl. & Diels
Kenya, Tanzania, Malawi, Zambia,
Angola, Botswana, Zimbabwe,
Mozambique and South Africa
Root, stem bark and leaves are
used as decoctions, macerations
and baths, leaf sap, soup of roots
cooked with chicken, leaf sap
mixed with leaf sap of Diospyros
zombensis (B.L. Burtt) F. White,
leaves and fruits as vegetables
Venereal diseases, sores, wounds,
dysentery, menorrhagia, swellings of
the stomach, wounds, muscle pain,
and diarrhea
[17,92–94]
P. suberosa Engl. & Diels
West Africa; Mali, Senegal, Guinea,
Ghana, Togo, Benin, and Nigeria
Leaves, leafy twig infusions, root
decoctions, roasted pulverized
root is used topically for
headache, extracts of chopped
roots and young shoots, stem
bark, and young branches are
used as chew sticks
Called “Terenifu” in Malian
traditional medicine
Meningitis, convulsive fever,
headache, jaundice, dysentery,
dermatitis, stomachache, gastric
ulcers, purgative, toothache,
hemorrhoids, conjunctivitis, trachoma,
gastrich ulcers, cataract, cough
medicine, sexually transmitted
diseases, hemorrhoids, viral diseases,
and candidiasis
[24,95–104]
Abbreviations: HIV—Human Immunodeficiency Virus; DR Congo—Democratic Republic of Congo.
The leaves of C. apiculatum are used for the disinfection of the navel after childbirth,
and decoctions of the leaves are taken in combination with steam bath treatments for
stomach problems [70]. The stem bark is used for conjunctivitis [35].
C. collinum (Variable bushwillow) has a wide geographical occurrence in tropical and
subtropical Africa [67]. It is a small, semi-evergreen tree or coppicing shrub [86] with a very
variable morphology; several subspecies have been distinguished [72]. The bark is reddish
brown to pale yellow, and the leaves are very variable in size, reaching sizes of up to 22 cm
in length and 8 cm in width. The fragrant, yellow, cream, or white flowers are arranged in
spikes; the winged fruit is a reddish brown to dark brown with a metallic appearance [67].
C. collinum is used together with Combretum molle and Phyllanthus reticulatus (Euphorbiaceae)
to treat diarrhea [71]. The roots are made into decoctions for the treatment of dysentery [69].
Decoctions of the leaves are used to treat chronic diarrhea [53].
C. hartmannianum has a geographical occurrence restricted mainly to the Horn of
Africa (Sudan, Ethiopia, Eritrea, and South Sudan) [73,105]. It grows into a shrub or small
tree in the savanna woodlands, high-rainfall savannas, and wooded grasslands. The crown
is broad and dense, and the shape of the leaves are characteristic for this species, having
extremely extended tips [106]. The stem bark, roots, and leaves of this plant are used to
treat jaundice [74]. In Sudan, the leaves are used as an ingredient in a medication used for
jaundice, and smoke from the wood and bark is used to treat rheumatoid arthritis and dry
skin [64,75]. Moreover, in Sudan, decoctions, macerations, and ethanolic tonics of the root
and stem wood are used to treat a persistent cough, a symptom that could be related to
tuberculosis [76]. In addition, C. hartmannianum is reported to be used for the treatment of
fever and bacterial infections in Sudanese traditional medicine [77].
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C. hereroense (russet bushwillow) is native to Angola, Botswana, Caprivi Strip, Ethiopia,
Kenya, KwaZulu-Natal, Malawi, Mozambique, Namibia, Northern Provinces, Somalia,
Sudan, Eswatini, Tanzania, Uganda, Zambia, and Zimbabwe. C. hereroense occurs in
wooded grasslands (Figure 2A) and in Acacia-Commiphora bushlands. It is a small tree
(8–12 m tall) or coppicing shrub. The leaves tend to cluster towards the ends of the twigs.
The inflorescences (axillary spikes) often appear on leafless shoots, and the flowers are
pale yellow to yellow and fragrant. The four-winged samara fruit is dark reddish to
brown [67]. Decoctions of the root and young stem are taken as an oral medication in
Namibian traditional medicine to treat tuberculosis, coughs, gonorrhea, and diarrhea [54].
In Zimbabwe, C. hereroense is used for the treatment of bilharzia [51]. Root decoctions are
used for schistosomiasis and leprosy [69], and the shoots are used for toncillitis [79].
C. kraussii (syn. C. nelsonii Duemmer, C. woodii Duemmer, forest bushwillow) is native
to southern Africa, where it occurs in the Cape Provinces, KwaZulu-Natal, Mozambique,
Northern Provinces, and Eswatini. It grows as a shrub or small tree in forests and forest
margins. The leaves are bright red in the winter and are narrowly to broadly elliptic with
an entire but wavy margin. The leaf lamina can be up to 9 cm long. In association with the
inflorscences, there is often a flush of new, whitish, smaller leaves. The greenish to creamy
white flowers can number up to fifty in dense axillary heads. The fruit is a four-winged
samara with a yellowish color and dark red wings [86]. The leaves of C. kraussii are applied
to wounds, and leaf extracts are used for the treatment of respiratory diseases [22,81,82].
C. nigricans occurs from west tropical Africa to Ethiopia, where it grows in savanna
regions and forest fringes. It is a small tree, growing up to 10 m. The bole is often twisted,
and the bark is smooth. Two varieties occur: var. nigricans, with pubescent, leafy stems;
and var. elliottii, with glabrous, leafy stems. During the hot season, the bark yields a
gum, known as chiriri in Hausa, which is traded in the Sudano-Guinean region [66,87].
In Senegal, the bark and leaves are used as a cough medicine and expectorant [66]. An
aqueous macerate is taken for colic and intestinal problems. The gum exudate from the
stem is used for intestinal disorders, acne, jaundice, and rheumatism [64]. In Nigeria, the
leaves are used to treat malaria [88].
C. padoides (thicket bushwillow) grows in the lowland areas of tropical and southeastern Africa. It occurs in many habitats, from muddy riverbanks and dry woodlands
to dry, rocky hillsides. Thicket bushwillow grows into a tree with drooping branches or
a many-stemmed shrub. The leaves are arranged oppositely to suboppositely and have
an acuminate apex. The flowers are a white to yellowish color and are arranged in spikes
that can be up to 10 cm long. The four-winged fruits have a circular shape [67]. The name
“padoides” comes from its resemblance to Padus spp. (Rosaceae). In traditional medicine,
the leaves and roots are made into decoctions and cold-water extracts or the crushed leaves
are used for bloody diarrhea, wounds, conjunctivitis, and malaria [80,88,89].
C. pentagonum is a liana or tree that grows in the seasonally dry tropical biome in
eastern and southern tropical Africa. Root decoctions are used for hernia, hookworms,
and dropsy. Root decoctions are mixed with porridge for the treatment of gonorrhea. In
addition, root decoctions are used as a mouth rinse to treat bleeding gums and loosening
teeth. Leaf decoctions are mixed with porridge for the treatment of gonorrhea [71].
C. psidioides (Peeling twig Combretum) grows to a tree (up to 17 m tall) or a large
shrub in woodlands with sandy soils. The branchlets are usually tomentose when young,
with bark that peels off in long, grey to black–purple strips, leaving a cinnamon-colored
surface. The leaves are large, obovate, soft, oppositely arranged, and have a lower surface
covered with dense hairs. In Tanzania, decoctions of the root of C. psidioides are used to
treat diarrhea and muscle pain. The leaves are pounded and mixed with a maize porridge
called Ugali to treat edema. In addition, C. psidioides is used in combination with C. molle
and C. zeyheri to treat chest problems, pains in the spinal cord, and oedema [36].
C. zeyheri (large-fruited bushwillow) is a smallto medium-sized deciduous tree with
a rounded crown. It occurs from Kenya to the DR Congo and the south to northeastern
parts of South Africa in dry forests, savanna woodlands (Brachystegia woodlands), wooded
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grasslands, riverbanks, and dunes, especially in sandy soils. It also often grows on termite
mounds. The size of the leaves and fruits of C. zeyheri is very variable. The branches
are light brown and hairy. The leaves are oppositely arranged or in whorls of three. The
flowers are greenish yellow and are arranged on spikes which can grow up to 8 cm long.
The fruits are large and almost circular, four-winged, with a light brown color (Figure 2C).
C. zeyheri has many uses in traditional medicine. The smoke of the leaves is inhaled to treat
coughs. Water extracts of the leaves are used to treat colic. In Zambia, the leaves and stem
bark are mixed with the roots of cassava to treat smallpox [59]. Decoctions of the leaves
are used to treat eye inflammations (conjunctivitis). In addition, the leaves are pounded
and mixed with oil for the treatment of back pain. Infusions and hot-water extracts of the
roots are mixed with porridge for the treatment of diarrhea, dysentery, and vomiting [35].
C. zeyheri was one of the most popular medicinal plants among traditional healers in the
Mbeya region, Tanzania, where decoctions of the leaves or roots are used as such or mixed
with porridge to treat diarrhea [36]. Moreover, traditional healers in Mbeya sometimes mix
C. zeyheri with other species of Combretum for the treatment of diarrhea [36].
3.2. The Genus Pteleopsis
3.2.1. Botany
There are nine species of Pteleopsis in tropical Africa [66]. Pteleopsis species are small- to
medium-sized trees or shrubs (Figure 3). In morphology, the genus is intermediatebetween
Combretum and Terminalia. For example, the leaves lack scales or stalked glands, as in
Combretum spp. The white-petaled flowers are arranged in terminal, axillary, or extraaxillary racemes, and hermaphrodite and male flowers are in the same inflorescence as
in Terminalia spp. The fruits are two- to four-winged. Pteleopsis species occur in coastal
bushlands, wooded grasslands, deciduous woodlands, riverine forests, and dry evergreen
forests [67].
Figure 3. Fruiting Pteleopsis myrtifolia. Photo: Pia Fyhrqvist.
3.2.2. Ethnopharmacology
Three species of Pteleopsis are used in African traditional medicine: P. myrtifolia in East
Africa and P. hylodendron and P. suberosa in West Africa [46] (Table 1).
Pteleopsis myrtifolia (also known as stink-bushwillow or two-winged stinkbush) occurs
in Kenya, Tanzania, Malawi, Zambia, Angola, Botswana, Zimbabwe, Mozambique, and
South Africa. It is the only species of Pteleopsis that occurs in South Africa. Growth habitats
of P. myrtifolia include evergreen and riverine forests and savanna woodlands. P. myrtifolia
is a semi-deciduous, small tree with drooping branches, reaching heights up to 20 (–30) m
(Figure 3) [66]. The bark is smooth, with a greyish pink color and a net-like appearance.
The myrtle-like leaves are opposite and simple, with a glabrous–hairy and shiny lamina.
The inflorescences are axillary to verticillate and contain both male and hermaphroditic
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flowers, white-petaled and strongly scented with an odor resembling honey or a strong
smell. The fruit is yellowish green, turning brown when ripe, and papery thin with two to
five wings [17]. A root decoction is taken to treat dysentery and stomachache, excessive
menstruation, intestinal worms, and for fever [17]. Roots are boiled in water, and the
decoction is drunk thrice a day for venereal diseases. It is applied externally to sores
and wounds. Roots and leaf sap are used for the treatment of venereal diseases; the
decoction is drunk against dysentery, menorrhagia, swellings of the stomach, and for
treating wounds [17]. Roots, stem bark, and leaves are used for muscle pain and diarrhea
as cold macerations, administered orally and as baths [92]. In Tanzania, the leaf sap of
P. myrtifolia is drunk together with the leaf sap of Diospyros zombensis (B.L. Burtt) F. White
(Ebenaceae) to treat dysentery. The roots are cooked with chicken, and the soup is taken to
treat sterility. P. myrtifolia is also used as a medicine for female sterility [52]. In addition,
P. myrtifolia is used for malaria in Mozambique, although the antimalarial properties are
still unknown, and should thus be studied to validate this therapeutic use [92]. The leaves
and fruits are considered edible, as a vegetable [93]. In Maputaland, a natural region in
South Africa, the smoke of the wood is used to preserve food [94]. The leaves and roots of
P. myrtifolia are only sold in local markets for medicine.
P. suberosa occurs in the savanna region of West Africa, and occurrences are recorded
from Mali, Senegal, Guinea, Ghana, Togo, Benin, and Nigeria [95]. P. suberosa is a deciduous
shrub or a small tree, growing between 6 and 10 m tall. The bark is distinctively covered
with corky warts [96]. The leaves are sometimes alternate, slightly short-haired, and
greyish green. The flowers are greenish yellow, while the fruits are winged and pale
green, becoming brown at maturity. The leaves of P. suberosa are popularly known for
the treatment of meningitis, convulsive fever, and headache; they are also used to treat
jaundice and dysentery [95]. A decoction of the fresh roots is used as a medicine against
dysentery, dermatitis, stomachache, and gastric ulcers, and as a purgative [24]. Infusions
of the bark or the leafy twigs are taken to treat many diseases, such as jaundice, wounds,
toothache, hemorrhoids, conjunctivitis, trachoma, and cataracts [97,98]. The roots, leaves,
and stem barks of P. suberosa are used in the treatment of diabetes mellitus [99]. The
roasted, pulverized root is rubbed on the head to treat headaches. An extract from the
chopped roots and young shoots is taken as a cough medicine. Various parts of P. suberosa
are used in traditional medicine throughout West Africa [96]. According to a survey on
medicinal plants in the Ghanaian herbal markets, P. suberosa were the most frequently sold
medicinal products [99]. The stem bark strips are sold with the medicinal indication, “to
cleanse the uterus and to treat sexually transmitted diseases” [99]. In addition, the bark of
P. suberosa is commonly used in Mali for the treatment of gastric ulcers [100]. Moreover,
in the Malian folk medicine, the stem bark, commonly named “terenifu”, is known as a
traditional remedy against coughs, asthma, hemorrhoids, viral infections, and especially
against ulcers. In Benin, the decoction of roots is used by traditional healers as a treatment
for various diseases and conditions. The stem bark is used to treat dysentery, eruptive fever,
and epilepsy [101,102]. P. suberosa is sold at the local traditional markets of southern Benin
for the treatment of candidiasis [103], and for oral diseases in Burkina Faso [104]. Young
branches are used as chew sticks.
P. hylodendron is a tree commonly found in the forest regions of West and Central
Africa and in Cameroon. The tree can grow up to 25–40 m tall, occasionally reaching 50 m.
It resembles—and may be confused—with Terminalia ivorensis. The aqueous decoction of
the stem bark of P. hylodendron is used to treat measles, chickenpox, sexually transmitted
diseases, female sterility, and liver and kidney disorders [90,91]. In Congo, the leaf sap is
used as a wash to treat epilepsy.
4. Antibacterial and Antifungal Properties
A number of African Combretum species and some Pteleopsis species have been studied
for their in vitro antibacterial and antifungal effects. The numbers of these studies has
increased recently. The species of Combretum are better studied, whereas fewer studies
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are available on the Pteleopsis species. However, there are still many species that have
not been studied in this regard. Several studies have mainly examined the effects of
different extracts, while studies dealing with antimicrobial compounds from the species of
Combretum and Pteleopsis are less common. Moreover, some antimicrobial screening studies
cited in this review involved an ethnomedicinal component to facilitate the selection of
plant species for the screenings and to verify the claimed folk-medicinal value of the plants
to treat infectious diseases and other infections. However, there are still a large number of
antimicrobial screenings of Combretaceae that did not include an ethnomedical selection
of suitable plant species [22]. While the antimicrobial potency has mostly been assessed
as the growth inhibitory effect, anti-biofilm effects were investigated in a few cases. A
variety of techniques, such as agar diffusion, agar dilution, and broth dilution methods,
have been used to detect antimicrobial activities. In addition, the microbial growth has
been assessed using turbidity (optical density) or reagents that measure cellular respiration
(such as tetrazolium salts and resazurin).
4.1. Antibacterial and Antifungal Effects of Combretum spp. Extracts
In Table 2, African species of Combretum that have been screened for their antibacterial
and/or antifungal effects are summarized. The species were chosen for more in-depth
discussions according to the number of studies referring to them in the ScienceDirect
database. In some studies, species with a common occurrence in South Africa and with
many uses in traditional medicine, including treating infections, have been screened
for their antibacterial and antifungal properties [13,22,107,108]. Some studies have included a large number of species. Masoko et al. [108] screened twenty-four South African
species for their antifungal effects, Eloff [107] screened twenty-one species for their antibacterial effects, and Anokwuru et al. [109] screened twenty-eight species of Combretum
against a panel of human pathogenic bacteria. Most studies on the antibacterial effects
of Combretum species on bacteria that cause respiratory diseases have used only one bacterium, either Pseudomonas aeruginosa or Klebsiella pneumoniae, although a multitude of bacterial strains, such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza,
Corynebacterium diphteriae, Bordetella pertussis, and Mycobacterium tuberculosis are known
to cause respiratory diseases [22]. Moreover, to date, C. psidioides, C. padoides, C. zeyheri,
C. hartmannianum, C. molle, C. apiculatum, C. imberbe, and C. hereroense are the species
that have so far been screened for their antimycobacterial effects, although there are still
many Combretum species used for tuberculosis (TB) that have not been scientifically validated [23,51,107,110–113]. For example, C. micranthum is used for TB in Guinean traditional
medicine, but there is no literature available about its antimycobacterial potential.
The antibacterial and antifungal potency of African Combretum species varies significantly between different species, plant parts, and extracts, as well as with the growth locality
(Table 2). MIC values from 0.009 mg/mL up to 5 mg/mL, and sometimes even higher
values (>6 mg/mL), are reported. However, in general, organic extracts of Combretum spp.
have been reported to be more active than aqueous extracts [19]. Exceptions to this are
known, such as a water extract of the leaves of C. molle, which inhibited the growth of
Fusarium spp. (F. proliferetum, F. solani) with an MIC value of 40 µg/mL [19]. Moreover,
extracts from a broad range of polarities have shown good antibacterial and antifungal
activities; therefore, antimicrobial compounds in Combretum spp. are found both among
non-polar, medium-polar, and polar compounds [28,114]. Regarding plant extracts in
general, extracts demonstrating MIC values lower than 100 µg/mL are regarded as strongly
active, while extracts possessing MIC values between 100 and 500 µg/mL are regarded
active [115]. As can be seen from Table 2, extracts of several species of Combretum showed
strong antibacterial and/or antifungal activity, with MIC values well below 100 µg/mL. In
addition, numerous species have MIC values within the 100 to 500 µg/mL range [15,28].
In some cases, the Combretum species were selected for antibacterial or antifungal assays
due to their uses for the treatment of topical or internal infections in African traditional
medicine. In addition, species with no known (documented) ethnopharmacological uses
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have been screened. In this review, species of Combretum that are important in African
traditional medicine, and which have many documented uses for the treatment of infections
and their symptoms, are discussed in more detail to summarize the screening results on
their in vitro antimicrobial effects.
Table 2. Antibacterial and antifungal effects of extracts of African Combretum species.
Plant Extracts
MIC/IZ/IZD
Reference
C. acutifolium Exell. (leaf)
Acetone, hexane, DCM, and methanol extracts
MIC range: 0.02–2.5 mg/mL against C. albicans, C. neoformans,
A. fumigatus, S. schenckii, and M. canis.
[108]
C. acutifolium (leaf)
Methanol extract
MIC range: 0.15–1.50 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae.
[109]
C.adenogonium Steud ex A.Rich syn. C. fragrans F.
Hoffm. (leaf)
Water, methanol, and n-hexane
MIC values: 1 mg/mL (B. cereus, K. pneumoniae),
0.01562 mg/mL (B. cereus), and 0.25 mg/mL (S. aureus).
[116]
C. fragrans F. Hoffm. syn. C. adenogonium (leaf)
Ethanol extracts
MIC 0.25–4 mg/mL (Candida species)
MIC between 0.5 and >4 mg/mL (Filamentous micromycetes).
[117]
C. fragrans F. Hoffm. syn. C. adenogonium (root)
Methanol extracts
IZD between 0 and 38 mm (Gram-positive and Gram-negative
bacteria and Candida albicans).
Best result: 38 mm against Micrococcus luteus.
[36]
C. fragrans syn. C. adenogonium (root)
Methanol extracts
Antifungal against Candida albicans, C. krusei, C. glabrata,
C. parapsilosis, and Cryptococcus neoformans. Best result against
C. glabrata: IZD 26 mm.
[17]
C. adenogonium (leaf)
Acetone extracts
MIC 0.625 mg/mL (E. coli)
[118]
C. albopunctatum Suess. (leaf)
Acetone and hexane extracts
MIC 0.08 mg/mL (C. neoformans and A. fumigatus).
[108]
C. albopunctatum (leaf)
Methanol extracts
MIC range: 0.75–3 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae.
[109]
C. albopunctatum (leaf)
Acetone extracts
MIC values ranging between 0.02 and 0.64 mg/mL against
C. albicans, C. neoformans, M. canis, S. schenckii, and A. fumigatus.
[83]
C. albopunctatum (leaf, stem bark)
Water extracts
Stem bark and leaf extracts inhibit the QS-dependent
production of violacein and pyocyanin in
Chromobacterium violaceae and P. aeruginosa.
[119]
C. apiculatum Sond. subsp. apiculatum (leaf)
Ethanol and water extracts
MIC values of ethanol extracts: 0.049 mg/mL against B. subtilis
and S. aureus.
MIC values of water extracts: 0.39 mg/mL against B. subtilis
and S. aureus.
[120]
C. apiculatum ssp. apiculatum (leaf)
DCM, methanol, and acetone
MIC 0.04 mg/mL (C. albicans and C. neoformans),
[108]
C. apiculatum subsp. apiculatum (leaf)
Acetone extracts
MIC 1.6 mg/mL (P. aeruginosa), 0.4 mg/mL (S. aureus),
0.8 mg/mL (E. coli), and 0.8 mg/mL (E. faecalis).
[107]
C. bracteosum (Hochst.) Engl. & Diels (leaf)
DCM, methanol, and hexane
MIC 0.02 mg/mL (C. neoformans)
MIC 0.02 mg/mL (S. schenckii)
[108]
C. bracteosum(Hochst.) Brandis (leaf)
Methanol extracts
MIC range: 0.50–3.00 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae.
[109]
C. caffrum (Eckl. & Zeyh.) Kuntze (leaf)
Hexane and DCM extracts
MIC 0.16 mg/mL (C. albicans, C. neoformans).
[108]
C. caffrum (leaf)
Acetone extracts
MIC values: 6 mg/mL (P. aeruginosa), 0.8 mg/mL (S. aureus),
1.6 mg/mL (E. coli), and 0.4 mg/mL (E. faecalis).
[107]
C. caffrum (leaf)
Methanol extracts
MIC range: 0.63–2.50 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae.
[109]
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Table 2. Cont.
Plant Extracts
MIC/IZ/IZD
Reference
MIC range between 0.02 and >2.5 mg/mL
C. albicans, C. neoformans, A. fumigatus, Sporotrichum schenkii,
and Microsporum canis.
Best results: DCM 0.08 mg/mL (C. neoformans); acetone and
MeOH 0.02 mg/mL (M. canis).
[108]
C. celastroides ssp. celastroides (leaf)
Acetone extracts
MIC values: 3.0 mg/mL (P. aeruginosa), 0.8 mg/mL (S. aureus),
3.0 mg/mL (E. coli), and 1.6 mg/mL (E. faecalis).
[107]
C. celastroides ssp. orientale (leaf)
Acetone extracts
MIC values: 1.6 mg/mL (P. aeruginosa), 1.6 mg/mL (S. aureus),
3.0 mg/mL (E. coli), and 0.8 mg/mL (E. faecalis).
[107]
C. celastroides subsp. celastroides and C. celastroides
subsp. orientale (leaf)
Methanol extracts
MIC range: 0.50–3.00 mg/mL and 0.25–3.00 mg/mL,
respectively, against S. aureus, B. cereus, S. epidermidis, E. faecalis,
E. coli, S. sonnei, S. typhimurium, P. aeruginosa, and K. pneumoniae.
[109]
C. collinum ssp. Suluense (Engl. & Diels) Okafor (leaf)
Acetone and DCM
MIC values: 0.08 mg/mL (C. albicans and C. neoformans).
[108]
C. collinum ssp. Taborense (Engl.) Okafor (leaf)
Acetone, DCM extracts
MIC values: 0.08 mg/mL (C. neoformans) and 0.64 mg/mL
(C. albicans).
[108]
C. collinum Fresen. (leaf)
Acetone extracts
MIC values: 0.13 mg/mL (S. aureus), 0.07 mg/mL (E. coli),
0.08 mg/mL (P. aeruginosa), and 0.100 mg/mL (E. faecalis).
[121]
C. collinum (fruits, leaves, roots)
Methanol extracts
No activity against Candida spp. or Cryptococcus neoformans,
with the exception of a leaf MeOH extract against C. krusei (IZD
18.4 mm).
[17]
C. edwardsii Exell (leaf)
Acetone and methanol extracts
MIC 0.04 mg/mL (C. albicans).
[108]
C. edwardsii (leaf)
Ethyl acetate fraction, DCM, hexane, and water fractions
MIC range from 0.390–3.125 mg/mL against E. coli,
K. pneumoniae, and S. aureus.
[30]
C. eleagnoides Klotzsch (leaf)
Methanol extracts
MIC 0.05 mg/mL against B. cereus and a low average MIC
value of 0.52 mg/mL against the other bacteria used in
the screenings.
[109]
C. erythrophyllum (Burch.) Sond. (leaf)
Ethyl acetate and acetone extracts
MIC 0.04 mg/mL (Fusarium spp.).
[19]
C. erythrophyllum (leaf)
Methanol extracts
MIC 3.875 mg/mL (C. albicans, A. niger).
[29]
C. erythrophyllum (leaf)
Acetone, methanol, DCM extracts
MIC values: 0.02 mg/mL (M. canis), 0.32 mg/mL (C. neoformans,
S. schenckii, and M. canis).
[108]
C. erythrophyllum (leaf)
Acetone extracts
MIC values: 3.0 mg/mL (P. aeruginosa), 0.8 mg/mL (S. aureus),
1.6 mg/mL (E. coli), and 1.6 mg/mL (E. faecalis).
[107]
C. erythrophyllum (leaf)
Methanol extracts
MIC range: 0.50–2.50 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae.
[109]
C. erythrophyllum (leaf)
Water, CHCl3 , butanol, 35% water in methanol, and CCl4
bioautography
MIC 0.05–25 mg/mL of solvent partition fractions against
S. aureus, P. aeruginosa, E. faecalis and E. coli
Best result for a 35% water extract in MeOH against S. aureus
(MIC 0.05 mg/mL); a chloroform fraction contained the highest
number of antibacterial compounds.
[114]
C. hartmannianum (Schweinf) (bark)
DCM, ethyl acetate, ethanol
MIC values of 12.5, 25 and 1.56 mg/mL, respectively, against
Mycobacterium aurum A+.
[112]
C. hartmannianum (bark)
Methanol, 50% ethanol
MIC values of 0.5 and 1 mg/mL, respectively, against
Porphyromonas gingivalis.
[122]
C. hartmannianum (fruit)
Water extracts
MIC 1.91 mg/mL, and IZD 20 and 19 mm against B. subtilis and
S. aureus, respectively.
[74]
C. hartmannianum (leaf)
Methanol extracts
MIC 1.43 mg/mL, IZD 30 mm against B. subtilis.
[74]
C. hartmannianum (leaf)
DCM, ethyl acetate, ethanol
MIC values of 0.78, 3.12 and 0.19 mg/mL, respectively, against
Mycobacterium aurum A+.
[112]
C. hartmannianum (root)
Ethanol extracts
MIC 0.2 mg/mL (E. coli, S. aureus).
[75]
C. celastroides ssp. celastroides Welw. ex M.A. Lawson
(leaf)
DCM, methanol, acetone, and hexane extracts
Antibiotics 2023, 12, 264
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Table 2. Cont.
Plant Extracts
MIC/IZ/IZD
Reference
C. hartmannianum (root)
MIC 0.313 and 0.625 mg/mL, respectively, of a methanol and
ethyl acetate extract of the root against
Mycobacterium smegmatis.
[76]
C. hereroense Schinz (leaf)
Acetone, methanol, DCM and hexane extracts
MIC values of 0.02 mg/mL (Cryptococcus neoformans),
0.02–0.32 mg/mL (Candida albicans), and 0.02–0.04 mg/mL
(Microsporum canis).
[108]
C. hereroense (leaf)
Hexane, DCM, acetone and methanol extracts
MIC values of 1.25, 0.62, 0.47 and 1.90 mg/mL, respectively,
against Mycobacterium smegmatis.
[113]
C. hereroense (leaf)
Acetone extracts
MIC values: 1.6 mg/mL (P. aeruginosa), 3.0 mg/mL (S. aureus),
3.0 mg/mL (E. coli), and 1.6 mg/mL (E. faecalis).
[107]
C. hereroense (leaf)
Methanol extracts
Water extracts
MIC values: 5.075 mg/mL (A. niger), 4.486 mg/mL (C. albicans),
0.395 mg/mL (Rhizopus stolonifer), 0.240 mg/mL
(Proteus vulgaris), and 0.287 mg/mL (Proteus vulgaris and
Rhizopus stolonifer).
[29]
C. hereroense (stem)
Methanol extracts
MIC values: 30.0 mg/mL (S. epidermidis) and 23.3 mg/mL
(Sarcina sp.).
[36]
C. imberbe Wawra (leaf)
Hexane, DCM
MIC 0.16 mg/mL (C. albicans and C. neoformans).
[108]
C. imberbe (leaf)
Acetone extracts
MIC values: 2.5 mg/mL (C. albicans), 0.16 mg/mL
(C. neoformans), 0.04 mg/mL (M. canis), and 2.5 mg/mL
(S. schenckii, A. fumigatus).
[83]
C. imberbe (leaf)
Methanol extracts
MIC range: 0.05–0.75 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae.
[109]
C. imberbe (leaf)
Acetone extracts
MIC values: 3.0 mg/mL (P. aeruginosa), 1.6 mg/mL (S. aureus),
3.0 mg/mL (E. coli), and 1.6 mg/mL (E. faecalis).
[107]
C. imberbe (leaf) Ethanol extracts
MIC 0.125 mg/mL (Mycobacterium smegmatis).
[51]
C. kraussii Hochst (bark)
Ethyl acetate, ethanol, and aqueous extracts
MIC values between 0.6–9.0 mg/mLagainst B. subtilis, S. aureus,
E. coli, and K. pneumoniae.
[123]
C. kraussii (leaf)
Hexane extracts
MIC 0.08 mg/mL (C. albicans)
[108]
C. kraussii (leaf)
Acetone extracts
MIC values: 1.6 mg/mL (P. aeruginosa), 0.8 mg/mL (S. aureus,
E. faecalis), and 1.6 mg/mL (E. coli).
[107]
C. kraussii (leaf)
Ethyl acetate fraction, DCM, hexane fraction, and water
fractions
MIC range from 0.390 to 1.560 mg/mL
against E. coli, K. pneumoniae, and S. aureus.
[30]
C. kraussii (root)
Ethyl acetate, ethanol, and aqueous extracts
MIC values between 0.195–3.125 mg/mLagainst B. subtilis,
S. aureus, E. coli, and K. pneumoniae.
[123]
C. micranthum G. Don (root, stem bark and leaves)
Water and methanol extracts
Agar diffusion IZD results: All root, bark, and stem bark
extracts showed a strong growth inhibition of clinical isolates of
P. aeruginosa at a level significantly higher than ampicillin,
gentamycin, and ciprofloxacin. Hot-water extracts of the root
bark inhibited the growth of clinical strains of
Streptococcus pyogenes. The root and stem bark extracts were
more active than extracts of the leaves.
[124]
C. micranthum (leaf)
Ethanol extracts
Active at 1 mg/mL and 5 mg/mL (P. aeruginosa and S. aureus)
and at 5 mg/mL against C. albicans (IZ from 8 to 11 mm). MIC
0.5 mg/mL of an ethanol extract of the leaves against S. aureus.
[84]
C. micranthum (leaf)
Acetone extracts
MIC 310 µg/mL (Mycoplasma mycoides subsp. mycoides).
[125]
C. micranthum (stem bark)
A 70% EtOH extract and its solvent partition fractions;
n-hexane, chloroform, and aqueous
70% EtOH extract and aqueous fraction: MIC 230 µg/mL
(E.coli), MIC 470 µg/mL (P. aeruginosa), and MIC 940 µg/mL
(S. aureus).
n-hexane fraction: MIC 7.5 mg/mL (S. aureus, E. coli), and
15 mg/mL (P. aeruginosa).
chloroform fraction: MIC 1880 µg/mL (S. aureus, B. subtilis, and
E. coli).
[126]
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Table 2. Cont.
Plant Extracts
MIC/IZ/IZD
Reference
C. microphyllum Klotzsch(leaf)
Acetone, methanol, DCM, and hexane extracts
MIC 0.02 mg/mL (C. neoformans)
[108]
C. microphyllum (leaf)
Acetone extracts
MIC values: 1.6 mg/mL (P. aeruginosa), 0.4 mg/mL (S. aureus),
0.8 mg/mL (E. coli), and 0.8 mg/mL (E. faecalis).
[107]
C. microphyllum (leaf)
Methanol extracts
3.9 mg/mL (A. niger), 1.008 mg/mL (C. albicans), and
0.494 mg/mL (R. stolonifer).
[29]
C. microphyllum (leaf)
Acetone and 1% aqueous sodium bicarbonate, hexane,
ethyl ether, methylene dichloride, tetrahydrofuran, acetone,
ethanol, ethyl acetate, methanol, and water.
MIC against S. aureus, P. aeruginosa, E. coli and
E. faecalis varied from 0.08 to 1.20 mg/mL for the different
extracts, with hexane providing the lowest MIC of 0.08 mg/mL
against E. faecalis. The water extract was not as active as the
other extracts (MIC 1.20 mg/mL).
[127]
C. moggii Excell (leaf)
Methanol extracts
MIC 0.02 mg/mL (C. albicans and C. neoformans).
[108]
C. moggii (leaf)
Acetone extracts
MIC 3.0 mg/mL (P. aeruginosa), 0.8 mg/mL (S. aureus),
1.6 mg/mL (E. coli), and 1.6 mg/mL (E. faecalis).
[107]
C. molle R. Br. ex. G. Don. (stem bark)
Acetone extracts
MIC 0.050 mg/mL (Shigella spp., E. coli)
[43]
C. molle (leaf)
Acetone extracts
MIC 0.625 mg/mL (E. coli)
[118]
C. molle (leaf)
Ethyl acetate and acetone extracts
MIC 0.04 mg/mL (Fusarium spp.)
[19]
C. molle (leaf)
Ethyl alcohol:H2 O (50:50)
MIC 0.25 mg/mL (Microsporum, Trichophyton)
[46]
C. molle (leaf)
Acetone, methanol, DCM and hexane
MIC 0.02 mg/mL (C. neoformans)
[108]
C. molle (leaf)
Acetone extracts
MIC 0.160 mg/mL (Mycoplasma mycoides subsp. mycoides)
[125]
C. molle (leaf)
Methanol extracts
IZD 0–30 mm. Best results: 30 mm against Micrococcus luteus,
25 mm against Enterobacter aerogenes, and 25 mm against
Sarcina sp.
[36]
C. molle (root)
Methanol extracts
MIC 1.00 mg/mL (S. aureus)
A decoction was inactive.
[128]
C. molle (stem bark)
Ethanol extracts
MIC 0.250 mg/mL (B. cereus)
[129]
C. molle (stem bark)
Acetone extracts
MIC 1.000 mg/mL (M. tuberculosis)
[111]
C. molle (leaf)
Methanol extracts
MIC 0.040 mg/mL against Penicillium janthinellum.
[130]
C. molle (root)
Methanol extracts
Antifungal against all Candida spp. used in the screening and
Cryptococcus neoformans. Best activity against C. glabrata (IZD
25.8 mm)
[17]
C. mossambicense (Klotzsch) (leaf)
Methanol and hexane extracts
Active against yeasts, dimorphic fungi and moulds at MIC
values between 0.02 and 2.5 mg/mL.
Lowest MIC values: 0.04 mg/mL of a methanol extract
(C. albicans); 0.02 mg/mL of acetone, dichloromethane and
hexane extracts (M. canis); and 0.02 mg/mL of a hexane extract
(C. neoformans).
[108]
MIC values: 0.800 mg/mL (P. aeruginosa, S. aureus),
1.600 mg/mL (E. coli), and 0.400 mg/mL (E. faecalis).
[107]
MIC 0.02 mg/mL (C. neoformans)
[108]
C. mossambicense (leaf)
Acetone extracts
C. nelsonii Duemmer (Angustimarginata Engl. & Diels)
syn. C. kraussii Hochst (leaf)
Hexane extracts
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Table 2. Cont.
Plant Extracts
MIC/IZ/IZD
Reference
C. nelsonii (leaf)
Acetone extracts
MIC values between 0.02 and 0.16 mg/mL against C. albicans,
C. neoformans, M. canis, S. schenckii and A. fumigatus.
[83]
C. nelsonii (leaf)
Acetone extracts
MIC values of 3.0 mg/mL (P. aeruginosa), 0.8 mg/mL (S. aureus),
1.6 mg/mL (E. coli), and 6.0 mg/mL (E. faecalis).
[107]
C. nigricans Lepr. (leaf)
Ethyl alcohol–water
(50:50, v/v)
MIC values between 1 and >4 mg/mL against C. albicans,
Epidermophyton floccosum, Microsporum gypseum,
Trichophyton mentagrophytes and Trichophyton rubrum.
[46]
C. nigricans (entire root)
Ethyl alcohol–water
(50:50, v/v)
MIC between 0.25 and >4 mg/mL against C. albicans,
Epidermophyton floccosum, Microsporum gypseum,
Trichophyton mentagrophytes and Trichophyton rubrum.
[46]
C. padoides Eng. & Diels (leaf)
DCM and acetone extracts
MIC 0.32 mg/mL (C. albicans, C. neoformans)
[108]
C. padoides (leaf)
70% Acetone in acidified water (crude), water, hexane,
ethyl acetate, and butanol fractions
MIC between 0.019 and 2.5 mg/mL against C. albicans,
C. neoformans, A. fumigatus, E. coli, E. faecalis, S. aureus, and
P. aeruginosa.
MIC values of various extracts:
Crude extract (70% acetone): 0.039 mg/mL (C. neoformans)
Hexane fraction: 0.019 mg/mL (E. coli, E. faecalis, S. aureus)
Ethyl acetate fraction: 0.019 mg/mL (C. neoformans)
Butanol fraction: 0.019 mg/mL (P. aeruginosa)
[117]
C. padoides (leaf)
Acetone extracts
MIC values: 0.800 mg/mL (P. aeruginosa, E. coli, and E. faecalis),
and 6.000 mg/mL (S. aureus).
[107]
C. padoides (root)
Methanol extracts
Antifungal against all Candida spp. and Cryptococcus neoformans.
Best result against C. glabrata; IZD 29.1 mm
MIC 6.25 mg/mL (C. glabrata and Cryptococcus neoformans)
[17]
C. padoides (stem bark)
Crude methanol extract and a butanol fraction resulting
from solvent partition of the MeOH extract
Lowest MIC: 1250 µg/mL of a methanol extract
MIC of a butanol fraction: 2.5 mg/mL
Test bacterium: Mycobacterium smegmatis
[23]
C. padoides (stem bark, root)
Methanol
IZD range: 0–32 mm
Best results: IZD 32 mm against Enterobacter aerogenes and
31 mm against S. aureus. Not active against E. coli.
[36]
C. paniculatum Vent. (leaf)
Acetone, methanol, DCM and hexane extracts
MIC 0.02 mg/mL (C. neoformans)
[108]
C. paniculatum (leaf)
Acetone extracts
MIC values: 1.6 mg/mL (P. aeruginosa, S. aureus, and E. faecalis),
0.8 mg/mL (E. coli).
[107]
C. paniculatum (root)
Methanol, water extracts
MIC values: 2.77 mg/mL (S. epidermidis), 1.85 mg/mL
(S. aureus), and 14.44 mg/mL (S. epidermidis, S. aureus).
[128]
C. pentagonum Laws. (fruit)
Methanol extracts
MIC 3.44 mg/mL, IZD = 21 mm, (B. subtilis)MIC 6.87 mg/mL,
IZD = 23 mm, (S. aureus)
[74]
C. pentagonum (bark)
Water extracts
MIC 4.86 mg/mL, IZD = 18 mm, (B. subtilis)
[74]
C. petrophilum Retief. (leaf)
Acetone, methanol, DCM, and hexane
MIC 0.02 mg/mL: acetone and methanol extracts against
C. albicans and M. canis; acetone, hexane, dichloromethane, and
methanol extracts against C. neoformans.
[108]
C. petrophilum (leaf)
Methanol extracts
MIC range: 0.50– >3.00 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae
[109]
C. psidioides Welw. (stem bark and fruit)
Methanol extracts
IZD 16.0–24.6 mm against C. krusei, C. glabrata, C. parapsilosis,
and Cryptococcus neoformans
[17]
C. psidioides (leaf)
Methanol extracts
IZD between 17–30 mm (diameter of hole: 12 mm) against
S. aureus, E. aerogenes, S. epidermidis, B. subtilis, and C. albicans
[36]
C. psidioides (stem bark)
Methanol extract and its n-butanol and chloroform
fractions resulting from solvent partition
IZD range: 14–29.00 mm, with the crude methanol extract being
the most active (IZD 29 mm).
Lowest MIC: 625 µg/mL of a methanol extract.
MIC 2500 µg/mL for the n-butanol and chloroform fractions.
Test bacterium: M. smegmatis
[23]
C. woodii Duemmer (leaf)
Hexane, DCM, methanol extracts
MIC values: 0.08 mg/mL (C. albicans and C. neoformans) and
0.02 mg/mL (Microsporum canis).
[108]
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Table 2. Cont.
Plant Extracts
MIC/IZ/IZD
Reference
C. woodii (leaf)
Crude water and methanol extracts
MIC values: 0.078 mg/mL (C. neoformans), 1.250 mg/mL
(C. albicans), 0.156 mg/mL (E. faecalis), 0.625 mg/mL (E. coli,
P. aeruginosa), and 0.312 mg/mL (S. aureus).
[117]
C. woodii (leaf)
Methanol extracts
MIC range: 0.50–3.00 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae.
[109]
C. zeyheri Sond. (leaf)
Methanol extracts
MIC range: 0.25–3.00 mg/mL against S. aureus, B. cereus,
S. epidermidis, E. faecalis, E. coli, S. sonnei, S. typhimurium,
P. aeruginosa, and K. pneumoniae.
[109]
C. zeyheri (entire plant)
Active at 0.03 mg/mL against C. albicans and
Trichophyton mentagrophytes. Screening with bioautography.
[131]
C. zeyheri (leaf)
Water and methanol extracts
MIC 6 mg/mL against E. coli and B. subtilis.
[132]
C. zeyheri (leaf)
Acetone and methanol extracts
MIC 0.02 mg/mL (C. albicans)
MIC 0.08 mg/mL (C. neoformans)
[108]
C. zeyheri (leaf)
Acetone extracts
MIC values: 0.80 mg/mL (P. aeruginosa and S. aureus) and
1.60 mg/mL (E. coli, E. faecalis).
[107]
C. zeyheri (stem bark, fruits, root)
Methanol extracts
IZD between 0–33 mm. Micrococcus luteus: IZD was 33 mm for
a stem bark methanol extract.
[36]
Abbreviations: IZD—inhibition zone diameter; IZ—inhibition zone; MIC—minimum inhibitory concentration,
DCM—dichloromethane; MeOH—methanol, EtOH—ethanol; CHCl3 —chloroform.
4.1.1. Combretum molle
The wide use of C. molle in African traditional medicine for the treatment of topical
and internal infections indicates that this plant contains antimicrobial compounds (Table 1).
In accordance with its traditional uses, C. molle extracts are reported to possess antibacterial
and antifungal activity against a large spectrum of bacterial and fungal strains [36]. The
screening results from various authors are summarized in Table 2. Most in vitro studies
have used the leaves and stem bark, while the roots are more seldom included, even
though the roots have traditional medicinal applications as decoctions and ointments
with antiseptic properties for the treatment of tuberculosis, skin diseases, and dysentery,
amongst others [36,37,111]. Elegami et al. [74] have reported that fruit extracts have an
antimicrobial activity, although the fruits of Combretum spp. are not usually recommended
to be used for traditional medicine, since they are considered poisonous.
An acetone extract of the stem bark showed an MIC value of 50 µg/mL against
E. coli and Shigella spp., which is the lowest reported MIC value of a C. molle extract
against bacteria. [43]. Moreover, MIC values of 160–170 µg/mL were observed for acetone
extracts of the leaves against P. aeruginosa and S. aureus [130]. Fyhrquist et al. [36] reported
that methanol extracts of the leaves inhibited the growth of E. aerogenes and S. aureus.
Ethanol extracts of the leaves and stem bark inhibited two clinical isolates of S. aureus and
Streptococcus agalactiae, both of which can cause bovine mastitis [81]. Ethanol extracts of
the stem bark of C. molle inhibited the growth of the food-pathogenic bacterium, B. cereus,
with an MIC of 250 µg/mL [129]. Leaf extracts in acetone were mildly active against E. coli,
with an MIC value of 625 µg/mL [118]. Moreover, mild growth-inhibitory effects were
recorded for an acetone extract of the stem bark against M. tuberculosis ATCC 27294, with
an MIC of 1000 µg/mL [111]. Additionally, a leaf extract inhibited Mycoplasma mycoides
with an MIC of 160 µg/mL [125]. Compared to the stem bark and leaves, few screenings
have used root material. For example, Steenkamp et al. [128] found that methanol extracts
of the root inhibited the growth of S. aureus (MIC 1 mg/mL), whereas a hot-water extract
(decoction) was inactive. These results support the uses of the C. molle leaf and stem bark
extracts for the treatment of infectious diseases and their symptoms in traditional medicine.
However, decoctions seem to be less effective when compared to ethanol extracts. Thus,
ethanol could be used as an alternative extractant for traditional remedies of C. molle.
Antibiotics 2023, 12, 264
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Several authors reported that extracts of C. molle inhibited the growth of both filamentous fungi and Candida species (Table 2). For example, Seepe et al. [19] found that the water,
ethyl acetate, and acetone extracts of the leaves of C. molle displayed promising antifungal
effects against Fusarium solanii and F. proliferetum, with an MIC value of 40 µg/mL for
all extracts. It was also noted that these effects were far better than for amphotericin-B
(MIC 370 µg/mL). The strong antifungal effect of the water extract is noteworthy; water
extracts of medicinal plants also have uses for the prevention and treatment of crop diseases among African smallholder farmers, as water is a readily available resource and the
leaves of C. molle are a sustainable and renewable source for antifungals [19]. Moreover,
Mogashoa et al. [130] found that an acetone extract of the leaves inhibited the growth of
the plant-pathogenic fungus Penicillium janthinellum with a MIC of 40 µg/mL. In addition,
Masoko et al. [108] found that acetone–leaf extracts were very good growth inhibitors
of Cryptococcus neoformans, with a MIC of 20 µg/mL. In their screening, Asres et al. [43]
found that an acetone stem-bark extract of C. molle inhibited C. albicans (MIC 400 µg/mL),
Aspergillus terreus (MIC 1200 µg/mL), and strains of Penicillium (MIC 1500 µg/mL against
all strains). Fyhrquist et al. [17] found that a methanol extract of the root was active against
all screened Candida spp. as well as Cryptococcus neoformans. Finally, ethyl alcohol: water
extracts (50:50) of the leaves of C. molle demonstrated good activity against the dermatophytes, Trichophyton mentagrophytes and Microsporum gypseum, which cause diseases on
human skin [46].
4.1.2. Combretum erythrophyllum
Although C. erythrophyllum is popular in southern African traditional medicine and is
used for many diseases and symptoms that could have a bacterial etiology, such as venereal
diseases, fewer studies report on its in vitro antimicrobial effects when compared to C. molle
(Table 2). Moreover, no studies exist so far on the antimycobacterial effects of C. erythrophyllum, although its stem bark, leaf, and root decoctions are used for coughs (Table 1).
Fresh leaf acetone extracts provided MIC values ranging between 0.8 and 3.0 mg/mL
against S. aureus, E. coli, P. aeruginosa, and Enterococcus faecalis [107]. Fractions obtained
from leaf material using solvent partition with CCl4 , CHCl3 , 35% water-in-MeOH, butanol,
and water were tested for their antibacterial effects, with the 35% water in methanol extract
showing the lowest MIC of 0.05 mg/mL against S. aureus [114]. Anokwuru et al. [109] found
that leaf methanol extracts of C. erythrophyllum were active against Salmonella typhimurium
and B. cereus, with MIC values ranging from 0.32 to 0.5 mg/mL. Martini et al. [60] isolated
several antibacterial flavonoids from a leaf extract of C. erythrohyllum. Acetone, hexane,
dichloromethane, and methanol extracts of the dried leaves of C. erythrophyllum were active
against Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Sporothrix schenckii,
and Microsporum canis, with MIC values ranging between 0.02 and >2.5 mg/mL [108].
In agreement with this finding, Cock and Van Vuuren [29] also observed that methanol
extracts of the leaves were active against C. albicans and Aspergillus niger. Additionally,
Seepe et al. [19] found that ethyl acetate and acetone extracts of the leaves of C. erythrophyllum showed promising growth-inhibitory effects against plant-pathogenic Fusarium
spp., with MIC values ranging from 0.04 to 0.08 mg/mL. In the same screening [19], water
extracts also showed activity against F. solani and F. proliferatum, though with slightly
higher MIC values (0.16 and 0.31 mg/mL, respectively) when compared to the ethyl acetate
(EtOAc) and acetone extracts.
4.1.3. Combretum adenogonium
Combretum adenogonium (syn. C. fragrans) has numerous uses in African traditional
medicine as a remedy against coughs, dysentery, diarrhea, septic wounds, and fungal
infections on the scalp [17,36,133] (Table 1). Accordingly, various authors have justified
these traditional uses (Table 2). Maregesi et al. [116] found that n-hexane and methanol
extracts of C. adenogonium exhibited strong antibacterial effects against B. cereus (MIC
15.62 µg/mL). Fyhrquist et al. [36] demonstrated that methanolic leaf and root extracts
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of C. fragrans (C. adenogonium syn. C. fragrans) were active against S. aureus, E. aerogenes,
S. epidermidis, B. subtilis, Micrococcus luteus, Sarcina sp., and C. albicans, with IZD values
for the leaves ranging between 18 and 34 mm and between 22 and 38 mm for the roots.
Additionally, Batawila et al. [117] showed in their screening that ethanolic extracts of
C. fragrans were active against ten Candida species, with MIC values between 0.25 and
4 mg/mL, and against ten filamentous fungi, with MIC values between 0.5 and >4 mg/mL.
4.1.4. Combretum hartmannianum
In the Sahel belt and in Sudan, C. hartmannianum is commonly used for the treatment
of sore throats, dysentery, fever, sexually transmitted diseases, fungal nail infections, skin
diseases, acne, wounds, ulcer infections, and leprosy (Table 1). All parts of the plant are
used, and common preparations include decoctions, macerations, tinctures, pastes, ointments, and teas. These traditional medicinal uses indicate that C. hartmannianum contains
antibacterial and antifungal compounds. Accordingly, some research has been performed
on the antimicrobial activity of extracts of various parts of C. hartmannianum (Table 2).
For example, bark extracts of Combretum hartmannianum demonstrated antibacterial activity against Porphyromonas gingivalis, a bacterium that causes periodontal diseases. The
methanol extract showed the best activity (MIC 0.5 mg/mL), whereas a 50% ethanol extract
was less active [122]. Water and methanol extracts of the stem bark, fruits, and leaves were
mildly active against B. cereus (with MIC values from 1.43 mg/mL to 4.19 mg/mL) and
S. aureus (with MIC values from 1.91 mg/mL to 8.39 mg/mL) [74]. In addition, ethanol,
ethyl acetate, and dichloromethane extracts of the root and leaf inhibited the growth of both
Gram-positive and Gram-negative bacteria at MIC values ranging from 0.1 to 3.13 mg/mL.
The best results were provided by a leaf dichloromethane extract (MIC < 0.1 mg/mL) and
a root dichloromethane extract (MIC 0.1 mg/mL) against B. subtilis. Moreover, ethanolic
root extracts of C. hartmannianum inhibited the growth of E. coli with an MIC value of
0.2 mg/mL [75]. Only two studies to date report on the antimycobacterial effects of C. hartmannianum. In a study by Eldeen and Van Staden [112], it was shown that leaf extracts
in particular, but also bark and root extracts, possessed growth-inhibitory effects against
Mycobacterium aurum, with a leaf ethanol extract demonstratinging the best effects (an MIC
of 0.19 mg/mL) followed by a stembark dichloromethane extract (an MIC of 0.78 mg/mL).
Moreover, Salih et al. [76] showed that methanol and ethylacetate extracts of the root are
active against M. smegmatis.
4.1.5. Combretum zeyheri
In accordance with the traditional medicinal uses of C. zeyheri throughout Africa for
diarrhea, coughs, eyewashes, toothaches, and bacterial and fungal infections (Table 1), a
number of authors have found that extracts of this plant possess in vitro antibacterial and
antifungal effects (Table 2). However, the MIC values reported against bacteria are in general quite high, and better growth-inhibitory effects were reported against fungi. Methanolic
extracts of the dried entire plant of C. zeyheri were active against C. albicans and Trichophyton
mentagrophytes at a concentration of 0.03 mg/mL when screened using a bioautographic
method [131]. Acetone, hexane, methylene dichloride, and methanolic extracts of the dried
leaves showed antifungal activities against Candida albicans, Cryptococcus neoformans, and
Aspergillus fumigatus, with MIC values between 0.02 and 2.5 mg/mL [108]. Accordingly,
Fyhrquist et al. [17] found that methanolic root and stem bark extracts had antifungal
activities, particularly against the Candida species used in their screening, such as C. albicans,
C. krusei, and C. tropicalis, as well as against Cryptococcus neoformans. Mapfunde et al. [134]
found that, at 200 µg/mL, various extracts of C. zeyheri, enriched in flavonoids, alkaloids,
and saponins as well as an ethanol extract of the leaves, inhibited the growth of C. albicans
by 48–87%. Moreover, an alkaloid-enriched extract was found to give the highest inhibition
(87%), followed by the ethanol extract (76%). However, the highest concentration used in
the screenings, 200 µg/mL, did not result in the MIC for any of the tested extracts.
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Water and methanol extracts of the dried leaves were active against E. coli and
B. subtilis only at high concentrations, with an MIC value of 6 mg/mL [132]. However, in the
same investigation, Masengu et al. [132] found that extracts of C. zeyheri leaves possessed
an inhibitory effect on rhodamine efflux. Therefore, they suggested that C. zeyheri contains
efflux-pump inhibitors that potentiate the antibacterial effects of compounds present in
medicinal plants that are often mixed with C. zeyheri for traditional remedies. Fyhrquist
et al. [36] showed that methanolic fruit, root, and stem bark extracts of C. zeyheri demonstrated antibacterial activity against S. aureus, Enterobacter aerogenes, S. epidermidis, B. subtilis,
Micrococcus luteus, Sarcina sp., and C. albicans, with IZD values between 15 and 33 mm.
However, the MIC values were not investigated in this investigation. Fyhrquist et al. [23]
showed that methanol and butanol extracts of the stem bark and butanol extracts of the
root of C. zeyheri inhibited the growth of Mycobacterium smegmatis. Additionally, Nyambuya
et al. [135] showed that an alkaloid-enriched extract of the leaves of C. zeyheri inhibited the
growth of M. smegmatis with an MIC value of 125 µg/mL, and the growth-inhibitory effect
was concentration- and time-dependent. The good antibacterial and antifungal results of
the alkaloid-enriched extracts [134,135] warrant more in-depth research on the antimicrobial alkaloids in C. zeyheri. Moreover, compounds with efflux-pump inhibitory activity
should be characterized.
4.1.6. Combretum micranthum
C. micranthum is used traditionally for the treatment of a variety of infections and is
believed to have antibacterial properties [13], Table 1. In accordance with its uses for fever,
coughs, bronchitis, burns, and wounds, and as a general antibiotic [45,84,85], extracts of
C. micranthum have shown antibacterial and antifungal effects. Aqueous and methanol
extracts of the stem bark, leaves, and root bark were screened against 200 clinical isolates
of nosocomial bacteria [124]. All the bark extracts showed a strong growth inhibition of
P. aeruginosa at a level significantly higher than ampicillin, gentamycin, and ciprofloxacin.
The screened P. aeruginosa isolates were susceptible to the hot-water extracts of the root
bark and stem bark of C. micranthum. Additionally, the hot water extract of the root bark
also significantly inhibited the growth of Streptococcus pyogenes.
Ethanolic extracts (70% ethanol) of the stem bark of C. micranthum, collected in Nigeria,
showed antibacterial effects against E. coli and P. aeruginosa, with MIC values of 230 and
470 µg/mL, respectively, and the same MIC values were also demonstrated by the aqueous
solvent partition fraction of the ethanolic extract [126]. In contrast, the n-hexane fraction
showed antibacterial activity only at high concentrations, with MIC values ranging from
7.5 to 15 mg/mL, whereas a chloroform fraction showed an MIC value of 1880 µg/mL
against S. aureus, E. coli, and B. subtilis.
The fresh leaf extract of C. micranthum was bactericidal against Shigella dysenteriae,
Salmonella parathyphi B, and Klebsiella ozaenae. It was bacteriostatic against Shigella flexneri,
S. boydii, Salmonella typhi, Klebsiella pneumoniae, and S. aureus [136], thus supporting its
traditional uses for diarrhea. The minimum inhibitory concentration of the ethanol extract
and the n-hexane, chloroform, ethyl acetate, n-butanol, and aqueous fractions of C. micranthum leaves ranged from 0.62 to 15 mg/mL against S. aureus, P. aeruginosa, K. pneumoniae,
Candida albicans, and Trichophyton rubrum [137]. The most purified fractions of C. micranthum leaves showed growth-inhibitory activity against methicillin-resistant Staphylococcus
aureus (MRSA), Clostridium difficile, E. coli, and P. aeruginosa, with MIC values of 625, 156,
1250, and 1250 µg/mL, respectively [138].
4.1.7. South African and Sudano-Sahelian Species of Combretum
In addition to the species discussed in detail in the previous paragraphs, a number
of other Combretum species with good antibacterial potential are listed in Table 2. Many
of these species have a geographical occurrence in southern and South Africa or in the
Sudano-Sahelian region.
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Methanol, dichloromethane, and n- hexane extracts of C. acutifolium were antibacterial and antifungal [108,109]. Several authors have found that the leaf extracts of
C. albopunctatum show antibacterial and antifungal potential [83,108,109,119]. Leaf extracts of C. apiculatum inhibited both bacterial and fungal growth [107,108,120]. Methanol
and dichloromethane extracts of the leaves of C. bracteosum showed strong antifungal
effects against Sporothrix schenkii and Cryptococcus neoformans, with an MIC value of
20 µg/mL [108,109]. C. collinum leaf extracts were antibacterial, demonstrating good
activity against E. coli (with an MIC of 70 µg/mL), and antifungal effects [17,108,121]. Leaf
dichloromethane extracts of C. celastroides ssp. celastroides demonstrated potent antifungal
effects against C. neoformans (MIC 90 µg/mL) and M. canis (MIC 20 µg/mL) [108]. Leaf
extracts of C. celastroides ssp. celastroides and C. celastroides ssp. orientale were antibacterial,
with activity profiles that slightly varied between extracts [107]. Combretum kraussii (syn.
C. nelsonii) bark and root extracts had antibacterial effects [123]. Leaf extracts of C. kraussii were antibacterial and antifungal, with an n-hexane extract being particularly active
against C. albicans (MIC 80 µg/mL) [108]. The antimicrobial effects of C. kraussii justify
the traditional medicinal uses of this species for the treatment of wounds and bacterial
infections [30,107,108]. C. microphyllum leaf extracts were antifungal, with the lowest MIC
of 20 µg/mL against Cryptococcus neoformans [29,108]. In addition, leaf extracts of C. microphyllum were active against E. faecalis, with a lowest MIC value of 80 µg/mL [107,127].
4.2. Antibacterial and Antifungal Effects of Pteleopsis Species
Studies on the antibacterial properties of African Pteleopsis species are shown in
Table 3. Although only three species—P. myrtifolia, P. hylodendron, and P. suberosa—are used
in African traditional medicine, some additional Pteleopsis spp., such as P. habeensis, have
also been studied for their antimicrobial potential.
4.2.1. Pteleopsis hylodendron
An ethyl acetate extract from the stem bark of Pteleopsis hylodendron growing in West
and Central Africa showed antibacterial effects against Salmonella typhi, Corynebacterium
diptheriae, Klebsiella pneumoniae, Proteus mirabilis, P. aeruginosa, Streptococcus pyogenes, and
Bacillus cereus [90]. Additionally, a methanolic stem bark extract of P. hylodendron demonstrated antibacterial effects against S. aureus (IZD 20.00–25.00 mm) and showed antioxidant
effects [139].
4.2.2. Pteleopsis habeensis
A 70% methanol extract of the stem bark of the West African species P. habeensis was
active against E. coli and methicillin-resistant Staphylococcus aureus (MRSA) [140].
4.2.3. Pteleopsis suberosa
Methanol extracts of the West African species Pteleopsis suberosa were found to possess antimicrobial activity against some skin-infection-causing bacteria, such as Staphylococcus aureus,
Staphylococcus capitis, S. epidermidis, Staphylococcus saprophyticus, Bacillus subtilis, Pseudomonas aeruginosa, and Pseudomonas cepacia [141]. The methanol extract and a decoction of
the stem bark of P. suberosa inhibited the growth of Helicobacter pylori ATCC 43504 and five
clinical isolates of this bacterium known to cause gastric ulcers [142]. This finding supports
the traditional use of decoctions from P. suberosa to treat gastric ulcers. Moreover, the use of
P. suberosa for the treatment of gastric ulcers could be supported by the finding that aqueous
extracts of the bark of P. suberosa contain high quantities of triterpenoid saponins that
protect the gastric mucosa against ethanol and indomethacin-induced gastric lesions [24].
The antifungal effects of ethyl alcohol–water (50:50, v/v) extracts of the stem bark were
observed in vitro against Candida albicans, Epidermophyton floccosum, Microsporum gypseum,
Trichophyton mentagrophytes, and T. rubrum [46].
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4.2.4. Pteleopsis myrtifolia
Decoctions of the root, leaves, and leaf sap of P. myrtifolia are used for the treatment
of wounds and bacterial infections, including dysentery. Some in vitro antimicrobial
screenings could justify these traditional uses. Interestingly, according to Anokwuru
et al. [109], methanol extracts of the leaves of P. myrtifolia were especially active against
bacteria related to food spoilage and food poisoning, such as Bacillus cereus, Shigella sonnei,
and Salmonella typhi (MIC 750 µg/mL). This result could support the use of P. myrtifolia
leaf decoctions for the treatment of dysentery. In addition, the leaf sap of P. myrtifolia,
combined with the leaf sap of Diospyros zombensis, is used for the treatment of dysentery.
Thus, this plant combination should also be tested for its antibacterial effect. A screening
made by Fyhrquist et al. [17] demonstrated that a methanol extract of the root of P. myrtifolia
inhibited the growth of all Candida spp. used in the study as well as Cryptococcus neoformans,
demonstrating the highest activity against C. glabrata. This study indicated that P. myrtifolia
contains antifungal compounds that should be studied in more detail.
Table 3. Pteleopsis extracts with antibacterial and antifungal properties.
Plant Extracts
MIC/IZ/IZD
Reference
Pteleopsis habeensis Aubrev ex Keay
(stem bark)
Methanol extracts
MIC/IZD against E. coli: 1.562 mg/mL (no growth), IZD
18–25 mm (at 12.5–100 mg/mL).
MIC/IZD against S. aureus:1.562 mg/mL (no growth),
IZD 18–24 mm (at 12.5–100 mg/mL).
[140]
Pteleopsis hylodendron Mildbr.
(stem bark)
Crude methanol extracts
MIC 0.781–12.5 mg/mL: E. coli, P. aeruginosa, P. mirabilis,
S. flexneri, S. paratyphi A/B, and S. typhi.
MIC 0.781–3.125 mg/mL: E. faecalis, S. aureus.
IZD against Gram-negative bacteria: 0.00–22.00 mm
IZD against Gram-positive bacteria: 10.87–25.00 mm
IZD against S. aureus (most sensitive): 20.00–25.00 mm
[139]
Pteleopsis hylodendron
(stem bark)
Ethyl acetate extract
Ethyl acetate extract of the stem bark active against
Salmonella typhi, Corynebacterium diptheriae,
Klebsiella pneumoniae, Proteus mirabilis, P. aeruginosa,
Streptococcus pyogenes, and Bacillus cereus.
[90]
Pteleopsis myrtifolia (M.A. Laws.) Engl. &
Diels.
(roots)
Methanol extracts
IZD 21.2 mm against C. glabrata
IZD 16.9–21.2 mm; C. albicans, C. krusei, C. tropicalis,
C. glabrata, C. parapsilosis, and C. neoformans.
[17]
Pteleopsis myrtifolia
(leaves)
Methanol extracts
Average MIC 1.85 mg/mL ± 0.88 mg/mL against both
Gram-positive and Gram-negative bacteria; S. aureus,
B. cereus, S. epidermidis, E. faecalis, E. coli, S. sonnei,
S. typhimurium, P. aeruginosa, and K. pneumoniae.
[109]
Pteleopsis suberosa Engl. et Diels
(stem bark)
Methanol extracts ad
decoctions
MIC-values: 0.03125–0.250 mg/mL and
0.0625–0.500 mg/mL, respectively, against
Helicobacter pylori (ATCC 43504), and five clinical
isolates of H. pylori.
[142]
Pteleopsis suberosa
(stem bark and shoots/twigs)
Ethyl alcohol–water (50:50, v/v)
MIC-values: 0.25–1 mg/mL (stem bark) and
0.25–2 mg/mL (shoot) against Candida albicans,
Epidermophyton floccosum, Microsporum gypseum,
Trichophyton mentagrophytes, and Trichophyton rubrum.
[46]
Pteleopsis suberosa
(stem bark)
Methanol extracts
Antimicrobial activity against some microorganisms
causing skin infections, such as Staphylococcus aureus,
Staphylococcus capitis, S. epidermidis,
Staphylococcus saprophyticus, Bacillus subtilis,
Pseudomonas aeruginosa, and Pseudomonas cepacia.
[141]
Abbreviations: IZD—diameter of inhibition zone; MIC—minimum inhibitory concentration.
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4.3. Antimicrobial Screenings Comparing Species Belonging to Two or More Genera
of Combretaceae
Papers including two or more genera of Combretaceae which were screened for their
antimicrobial effects are presented in Table 4. These studies allowed for a direct comparison
of the antimicrobial activities between closely related genera. There is a need for more
screenings using large panels of taxonomically related plant genera and species to directly
compare the antimicrobial potentials of different taxa [29]. Although this review focuses
mainly on the genera Combretum and Pteleopsis, the antibacterial activities of these genera
are compared to the closely related genera Terminalia and Quisqualis, also members of the
plant family Combretaceae. In many cases, African Terminalia species showed better average
antimicrobial effects than Combretum species [17,29,36], but also the opposite was seen in
some studies [109].
Table 4. Examples of antimicrobial screenings including Combretum, Pteleopsis, Quisqualis, and
Terminalia species (Combretaceae) to compare the antimicrobial effects within and between genera.
Parts of Plants and
Extracts
Bacterial and Fungal Strains
MIC Value Range and Most
Active Extracts
Reference
Fifty-one species were
screened: thirty-nine
Combretum spp., two
Pteleopsis spp.
and nine Terminalia spp.
Leaves;
methanol
Staphylococcus aureus, Bacillus
cereus, Staphylococcus epidermidis,
Enterococcus faecalis, Escherichia coli,
Shigella sonnei,
Salmonella typhimurium,
Pseudomonas aeruginosa, and
Klebsiella pneumoniae
MIC range: from 0.05 to
>3.00 mg/mL; MIC 0.05 mg/mL
for C. elaeagnoides and C. imberbe
against Salmonella enterica and
Shigella sonnei, respectively.
Combretum species more active
than Terminalia spp. and
Pteleopsis myrtifolia.
[109]
C. glutinosum, C. hispidum,
C. molle, C. nigricans,
P. suberosa, T. avicennioides,
and T. mollis
Leaves, shoot, and
stem bark
Ethyl alcohol–water
(50:50, v/v)
Candida albicans,
Epidermophyton floccosum,
Microsporum gypseum,
Trichophyton mentagrophytes, and
Trichophyton rubrum
MIC range: from 0.25 to
>4 mg/mL; 0.25 mg/mL for many
species against Epidermophyton
and Trichophyton.
P. suberosa most active.
[46]
Leaves;
water, and methanol
Twelve Gram-negative rods, two
Gram-positive rods, two
Gram-positive cocci, and
three fungi
MIC range: 0.031–6 mg/mL;
0.031 mg/mL for a water extract of
T. sericea against B. cereus.
Terminalia species were the
most active.
[29]
Staphylococcus aureus,
Escherichia coli,
Pseudomonas aeruginosa, and
Enterococcus faecalis
MIC range: 0.1–6 mg/mL.
Freshly made leaf extracts: MIC
0.2 mg/mL for T. brachystemma
and C. molle against S. aureus and
P. aeruginosa, respectively, and MIC
0.1 mg/mL for Q. littoria against
P. aeruginosa.
Stored leaf extracts: MIC
0.1 mg/mL for C. padoides and
C. nelsonii against P. aeruginosa.
[107]
Candida albicans, Candida krusei,
Candida tropicalis, Candida glabrata,
Candida parapsilosis, and
Cryptococcus neoformans
IZD from 0 mm to 32.2 mm. Best
results: T. sambesiaca, root, 32 mm
against C. glabrata; T. kaiserana,
root, 30.4 mm against C. glabrata.
C. padoides and C. molle methanol
root extracts gave good growth
inhibition, but were slightly less
active compared to the
Terminalia species.
P. myrtifolia was not as active as the
Combretum and Terminalia spp.
[17]
Plants
C. collinum,
C. erythrophloeum,
C. erythrophyllum,
C. hereroense,
C. microphyllum, C. molle,
T. prunioides, and T. sericea
Twenty-two Combretum
species, P. myrtifolia; three
Terminalia species
(T. branchystemma,
T. prunioides, and T. sericea);
and Quisqualis littoria
C. apiculatum, C. collinum,
C. constrictum, C. fragrans,
C. hereroense, C. molle,
C. obovatum, C. padoides,
C. psidioides, C. zeyheri,
P. myrtifolia, T. kaiserana,
T. sambesiaca, T. sericea,
T. spinosa, and
T. stenostachya
Leaves;
acetone
Leaves, roots, fruits,
stem bark;
acetone, ethanol,
methanol, and water
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Table 4. Cont.
Plants
Parts of Plants and
Extracts
Bacterial and Fungal Strains
MIC Value Range and Most
Active Extracts
Reference
C. fragrans, C. hereroense,
C. molle, C. padoides,
C. psidioides, C. zeyheri,
T. kaiserana, T. sambesiaca,
T. sericea, and
T. stenostachya
Leaves, roots, stem
bark, fruits;
methanol, acetone,
ethanol, and water
Staphylococcus aureus,
Escherichia coli,
Enterobacter aerogenes,
Staphylococcus epidermidis,
Bacillus subtilis, Micrococcus luteus,
Sarcina sp., and Candida albicans
IZD from 0 mm to 40 mm.
Best results:
Root extracts of T. sambesiaca,
T. kaiserana, T. sericea, and
C. fragrans.
[36]
C. imberbe, C. nelsonii, C.
albopunctatum, and
T. sericea
Leaves;
Acetone
Candida albicans,
Cryptococcus neoformans,
Microsporum canis, Sporothrix
schenckii, and Aspergillus fumigatus
MIC range from 0.02 to
0.64 mg/mL
Best result: C. nelsonii and T. sericea
leaf extracts with an average MIC
of 0.16 mg/mL.
[83]
Twenty-four Combretum
species
Leaves;
acetone, hexane, DCM,
and methanol
Candida albicans,
Cryptococcus neoformans,
Aspergillus fumigatus,
Sporothrix schenckii and
Microsporum canis
MIC range from 0.02 to
>2.5 mg/mL
Best result: methanol extracts of
C. moggii and C. petrophilum,
lowest MIC 0.02 mg/mL.
[108]
Abbreviations: MIC—minimum inhibition concentration; IZD—diameter of inhibition zone—DCM, dichloromethane.
In their recent study, Anokwuru et al. [109] screened the methanol leaf extracts of
fifty-one species belonging to the genera Combretum, Pteleopsis, Terminalia, and Quisqualis
for their antibacterial and antifungal effects. The background knowledge for this study was
that a number of African species of Combretaceae are used to treat bacterial and fungal
infections. Results from this screening indicated that Pteleopsis myrtifolia was not as active
as the Combretum and Terminalia spp. for its antibacterial and antifungal effects. The lowest
MIC values of 50 µg/mL was obtained by C. imberbe against Staphylococcus epidermidis and
C. elaegnoides against Shigella sonnei. Moreover, C. acutifolium, C. padoides, and C. nelsonii
displayed noteworthy activity against B. cereus (MIC 90–160 µg/mL). Compared to this, the
lowest MIC for Pteleopsis myrtifolia was 750 µg/mL, against B. cereus. In addition, C. imberbe,
C. acutifolium, and C. elaegnoides exhibited broad-spectrum antimicrobial activity with low
average MIC values against both Gram-negative and Gram-positive bacteria. When the
various genera were compared for their average MIC values, the genus Combretum exhibited
the lowest value, followed by Pteleopsis. Moreover, according to a biochemometric analysis,
the antimicrobial activity of those extracts displaying significant activity was related to their
triterpene and flavonoid contents. Of the species screened in this investigation, C. imberbe is
used commonly for diarrhea, while C. zeyheri and C. apiculatum are used for the treatment
of bloody diarrhea. In summary, the results from these screenings especially justify the use
of Combretum species for treatment of diarrhea.
In a study by Cock and Van Vuuren [29], methanol and water extracts of the leaves of
two Combretum spp. and six Terminalia spp. used in South African traditional medicine for
symptoms related to infections or infectious diseases were screened for their antibacterial
and antifungal activities. Both the inhibition zone diameters (IZD) and MIC values were
obtained with agar diffusion methods. All extracts showed broad-spectrum antibacterial
activity, inhibiting the growth of 75–100% of the tested bacterial strains. Moreover, the
Gram-positive and Gram-negative bacteria were approximately equally susceptible to
the extracts. In general, the Terminalia species showed better effects than the Combretum
species. The antibacterial effects of most of the extracts were mild, with MIC values
ranging between 200 and 5000 µg/mL. For the Combretum species, the methanol extracts
showed better activities than the water extracts against Gram-positive bacteria, whereas the
opposite was true for the Terminalia. The authors attributed the good activity of the water
extracts of Terminalia spp. to the high tannin content of these extracts. Moreover, when
compared to the Combretum extracts, the Terminalia extracts were more effective against the
Gram-negative bacteria. The best antibacterial effects were obtained with a water extract
of T. sericea, which demonstrated an MIC value of 31 µg/mL against B. cereus. This result
justifies the traditional medicinal use of macerations from the leaves of T. sericea to treat
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diarrhea. The best antifungal effects were obtained with methanol extracts of C. molle, which
showed MIC values of 126, 172, and 259 µg/mL against Aspergillus niger, Candida albicans,
and Rhizopus stolonifera, respectively. T. sericea methanol and water extracts showed the
best antifungal effects of the tested Terminalia spp., with MIC values of 215 and 235 µg/mL
against R. stolonifer.
In a comprehensive study, Eloff et al. [107] investigated acetone leaf extracts of twentyseven species of the genera Combretum, Terminalia, Pteleopsis and Quisqualis for their antibacterial effects against Staphylococcus aureus, Enterococcus faecialis, Pseudomonas aeruginosa and
Escherichia coli. All extracts inhibited the growth of both Gram-positive and Gram-negative
bacteria. However, the effects differed largely between species and between freshly made
and stored extracts (with six weeks of storage). In summary, the MIC values ranged from
0.1 to 6.0 mg/mL, with an average of 2.01 mg/mL. The mean MIC was 1.8 mg/mL against
Gram-positive bacteria, while it was 2.22 mg/mL against the Gram-negative strains. The
lowest MIC values were obtained with freshly made leaf extracts of Quisqualis littoria and
Combretum molle (MIC < 0.1 and 0.2 mg/mL, respectively, against P. aeruginosa) and Terminalia brachystemma (MIC < 0.2 mg/mL against S. aureus), and with stored extracts of Combretum
padoides and Combretum nelsonii against Pseudomonas aeruginosa (MIC < 0.1 mg/mL for both).
Terminalia sericea showed rather low MICs of 0.4 mg/mL against Enterococcus faecalis and
1.2 mg/mL against E. coli. The antibacterial results for C. molle, C. padoides, and C. nelsonii
could justify their use in African traditional medicine for the treatment of infections.
Fyhrquist et al. [36] combined an ethnomedical investigation on the medicinal use of
Combretaceae plants in Mbeya, Tanzania, with a screening of the antimicrobial activity of
extracts of Combretum and Terminalia species (hot water, methanol, acetone, and ethanol)
against Gram-negative and Gram-positive bacteria and C. albicans. The screening methods
used were the cylinder and the hole–plate agar diffusion methods. Almost all Combretum
and Terminalia extracts were active against Bacillus subtilis and S. aureus, but only T. kaiserana
demonstrated a growth-inhibitory effect against E. coli (bactericidal effect). Methanol
extracts of the roots of T. sambesiaca, T. kaiserana, and T. sericea displayed the largest inhibition
zone diameters (25–40 mm). When compared to the Terminalia spp., the Combretum spp.
were slightly less active, with the largest inhibition zone diameter shown by a root methanol
extract of C. fragrans against Micrococcus luteus. Moreover, both root and stem bark methanol
extracts of C. padoides showed good growth-inhibitory effects against a number of bacteria,
including S. aureus and E. aerogenes. Notably, many Combretum extracts were effective
against the Gram-negative E. aerogenes. These results support the ethnomedical uses of the
plants in the study for the treatment of infections and their symptoms.
In another study, Fyhrquist et al. [17] screened the antifungal effects of a large number
of Combretum and Terminalia species against yeasts (Candida spp.) and Cryptococcus neoformans. The most active species by far were T. sambesiaca and T. kaiserana, with IZD values of
32 and 30.3 mm, respectively, of their methanol root extracts against C. glabrata. Methanol
root extracts of C. molle and C. padoides were also particularly active against C. glabrata, with
slightly smaller inhibition zone diameters than compared to T. sambesiaca and T. kaiserana.
Elegami et al. [74] studied the antibacterial and antifungal effects of extracts from
Combretum hartmannianum, Terminalia arjuna, and Combretum pentagonum. These species
were selected based on their ethnomedical uses in Sudan for the treatment of wounds,
jaundice, and bronchitis. Aqueous extracts were prepared using the infusion method, which
is one of the methods used for the preparation of traditional remedies from Combretaceae in
African traditional medicine. Activities were determined using agar diffusion and dilution
methods, and extracts providing inhibition zone diameters of 15 mm were considered
active. The MIC values varied from 1.20 to 69.28 mg/mL. In terms of the MIC results, the
C. hartmannianum methanol extracts of the leaves and water extracts of the fruits provided
good growth inhibitory effects against B. subtilis (with MIC values of 1.43 and 1.91 mg/mL,
respectively). The methanol extracts of the fruits and leaves of T. arjuna provided moderate
growth inhibitory effects against B. subtilis and S. aureus, with MIC values of 2.89 and
2.43 mg/mL, respectively. Although C. pentagonum extracts provided rather high MIC
Antibiotics 2023, 12, 264
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values against the tested bacteria, methanol extracts of barks, leaves, and fruits resulted in
large inhibition zone diameters (21–23 mm) against B. subtilis, S. aureus, and E. coli. The
results of this investigation support the use of the screened plants for the treatment of
wounds (C. pentagonum) and bronchitis (T. arjuna). Moreover, the antibacterial effects of the
extracts were attributed to tannins and flavonoids.
In a comprehensive study, Masoko et al. [108] studied the antifungal effects against
Candida species and Cryptococcus neoformans of 24 species of Combretum. Acetone–leaf
extracts of C. moggii and C. petrophilum provided the lowest MIC value, 20 µg/mL.
5. Phytochemistry and Antimicrobial Compounds in Combretum and Pteleopsis spp.
Natural products have many modes of action relevant to antimicrobial potency. These
modes of action include the inhibition of proteins, lipids, RNA, DNA, and cell-wall synthesis. Moreover, plant-derived compounds can disrupt the membrane integrity and coagulate
the cell content. In addition, other modes of action include interference with microtubule
function (for example, anti-tubulin effects), the inhibition of cell division, interference
with ion uptake, the destabilization of the proton motive force (PMF), electron flow, active transport (drug efflux inhibition), reduction in protein secretion, dysfunction of RNA
processing, and the inhibition of DNA methylation [6,143,144]. Plant-derived compounds
also inhibit biofilm formation, bacterial motility and attachment, and the communication
between microbial cells (anti-quorum sensing). Flavonoids (catechins and naringenin),
ellagic acid, ellagic acid derivatives, and ellagitannins (cyclic-carbohydrate-containing ellagitannins, C-glycosidic ellagitannins with an open-chain glucose core, gallo-ellagitannins,
and flavano-ellagitannins) are often considered to be important phytochemicals with antimicrobial activity within the Combretaceae family [12]. However, regarding the genera
Combretum and Pteleopsis, only a few studies have been performed on ellagitannins and the
ellagic acid derivatives and/or their antimicrobial activity, although more studies exist on
the antimicrobial flavonoids in these genera. When considering the number of studies concerning antimicrobial compounds in Combretum and Pteleopsis, pentacyclic triterpenes have
been evaluated in many studies, and low MIC values are reported for some of them [13,26].
Additionally, within the genus Combretum, a number of stilbenes have been characterized,
of which some have demonstrated good antibacterial potential [145]. Table 5 summarizes
some of the studies that have been made on the phytochemistry of African Combretum and
Pteleopsis species with focus on antimicrobial compounds.
Table 5. Compounds in African species of Combretum and Pteleopsis and their antimicrobial potential.
Species
Compounds
Antimicrobial Activity
References
Triterpenes/triterpenoids and saponins
C. collinum
(leaf)
Olean-12-ene-3-one
Antibacterial activity against S. aureus and E. coli
with an MIC of 568.9 µg/mL.
[146]
C. imberbe
(leaf)
Imberbic acid, 1α,3β-hydroxyimberbic
acid-23-O-α-L-4acetylrhamnopyranoside, and
1α,3β,23-trihydroxy-olean-12-en-29-oic
acid-23-O-α-[3,4-diacetyl]rhamnopyranoside
An MIC of 1.56 µg/mL against Mycobacterium
fortuitum; an MIC of 3.13 µg/mL S. aureus; an MIC
of 12.5 µg/mL S. aureus;
an MIC of 12.5 µg/mL M. fortuitum;
and an MIC of 6.25 µg/mL S. aureus.
[147]
C. imberbe
(leaf)
1α,3β-dihydroxy-12-oleanen-29-oic
1-hydroxy-12-olean-30-oic acid,
3,30-dihydroxyl-12-oleanen-22-one,
1,3,24-trihydroxyl-12-olean-29-oic acid,
and
1α,23-dihydroxy-12-oleanen-29-oic acid3β-O-2,4-di-acetyl-L-rhamnopyranoside
MIC between 16 and >250 µg/mL against S. aureus,
E. faecalis, P. aeruginosa, and E. coli.
[26]
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Table 5. Cont.
Species
Compounds
Antimicrobial Activity
References
C. molle
(leaf)
Mollic acid–3-O-β-D–glucoside and
imberbic acid
Mollic acid–3-O-β-D–glucoside was not tested for
antimicrobial effects by Pegel & Rogers [148], but
Katerere et al. [147] showed that imberbic acid
inhibits M. fortuitum and S. aureus.
[147,148]
C. nelsonii syn. C. kraussii
(leaf)
Asiatic acid and arjunolic acid (in
antifungal TLC fractions from an acetone
extract; bioautography)
MIC of a mixture of asiatic acid and arjunolic acid
was between 0.2 and 1.6 µg/mL against C. albicans,
Cryptococcus neoformans, Microsporum canis,
Sporothrix schenckii, and Aspergillus fumigatus.
[82]
C. padoides
(leaf)
Triterpenoid desmosides, oleanane-type
triterpenoid glycosides, and
(25(27)-dehydroporiferasterol
Several of these compounds showed significant
antibacterial activity against S. aureus and E. coli.
[149]
C. racemosum (root)
Several triterpenoids:
(1) 28-O-β-D-glucopyranosyl2α,3β,21β,23-tetrahydroxy-olean-18-en-28-oate
(3) Arjungenin
(5) Terminolic acid
(11) 3-acetyl ursolic acid
(14) Betulinic acid
(15) Quadranoside II
Compound 1: MIC values of 128 and 256 µg/mL
against E. coli and E. faecalis.
Compounds 3, 5, and 11: MIC values between 64
and 256 µg/mL against S. aureus, E. coli and
E. faecalis.
[150]
C. zeyheri
(leaf)
Ursolic acid, oleanolic acid, maslinic acid,
2α,3β-dihydroxy-urs-12-en-28-oic acid,
6β-hydroxymaslinic acid, and
terminolic acid
All compounds showed anti-Candida activity of
which terminolic acid was most active; MIC values
between 62.50 and 125 µg/mL against strains of
C. albicans.
[151]
P. suberosa
(stem bark)
Ten oleanane-based saponins and three
aglycones; arjunglucoside I,
arjunglucoside II, sericoside, sericic acid,
arjunetin, trachelosperogenin,
bellericoside, and arjungenin
Arjunglucoside I was active against H. pylori
(ATCC 43504) and its metronidazole-resistant
strains (Ci 1 cag A, Ci 2 vac A, and Ci 3) with MIC
values between 1.9 and 7.8 µg/mL.
[95]
Tannins (hydrolysable and condensed
and related derivatives)
C. hartmannianum (bark)
Terchebulin and flavogallonic acid
MIC values of 500 and 1000 µg/mL against
Porphyromonas gingivalis.
[122]
C. hartmannianum
(root)
Terflavin B, terflavin B-isomer I, terflavin
B-isomer II, corilagin, (S)-flavogallonic
acid dilactone, tellimagrandin I,
α-punicalagin, terchebulin (or
β-punicalagin), and tellimagrandin
I derivative
MIC of 313 and 625 µg/mL, respectively, for a
methanol Soxhlet extract and an ethyl acetate
extract of the roots against
Mycobacterium smegmatis.
[76]
C. molle
(stem bark)
Punicalagin
Punicalagin totally inhibited the growth of
M. tuberculosis typus humanus ATCC 27294 at
concentrations higher than 600 µg/mL.
[111]
C. mucronatum (leaf)
A large number of condensed tannins;
epicatechin (1) and oligomeric
proanthocyanidins (OPC) 2–10
A dose-dependent anthelmintic activity ranging
from 1 to 1000 µM.
[152]
C. psidioides
(stem bark)
Epigallocatechin gallate (EGCG)
Present in a butanol extract of the stem bark that
showed antimycobacterial activity against
Mycobacterium smegmatis.
In another study [153], EGCG showed inhibition of
the cell-wall integrity of M. smegmatis.
Antibacterial against stains of Aeromonas and
Vibrio [154].
[23,153,154]
C. zeyheri, C. padoides and C.
psidioides
(stem bark and root)
Corilagin, punicalagin, sanguiin H-4, and
methyl ellagic acid xyloside as the main
components in C. psidioides stem bark;
ellagic acid arabinoside and ellagic acid
xyloside in C. padoides stem bark;
punicalagin, methyl-ellagic acid-xyloside,
di-methyl-ellagic acid xyloside, and
3,3′ -Di-O-methyl-4-O-(n′ ′ -O-galloyl-β-Dxylopyranosyl)- ellagic acid in
C. zeyheri
MIC values against Mycobacterium smegmatis:
Corilagin: 1000 µg/mL
Ellagic acid: 500 µg/ml
[23]
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Table 5. Cont.
Species
Compounds
Antimicrobial Activity
References
Flavonoids
C. albiflorum
Catechins
Inhibit transcription of quorum-sensing
related genes.
[119]
C. apiculatum (leaf)
Flawokawain A (4′ -hydroxy-2′ ,6′ dimethoxychalcone), pinocembrin (5,7dihydroxyflavanone), and alpinetin
(5-methoxy-7-hydroxyflavanone)
The isolated flavonoids were moderately active
against S. aureus and E. faecalis at MICs of
40 µg/mL.
[155]
C. apiculatum (leaf)
(1) 5,7-dihydroxyflavanone (pinocembrin)
(2) 2′ ,4′ -dihydroxy-6′ -methoxychalcone
(cardamomin)
(3) 5-hydroxy-7-methoxyflavanone
(alpinetin)
(4) 5,7-dihydroxyflavone (chrysin)
(1) MIC at 12.5 µg/mL against S. aureus and MIC
at 6.25 µg/mL against C. albicans;
(2) MIC from 100 µg/mL or higher against E. coli,
Mycobacterium fortuitum, Proteus vulgaris, and
S. aureus and MIC at 50 µg/mL against C. albicans;
(3) MIC at 25 µg/mL against C. albicans and
100 µg/mL against Proteus vulgaris and S. aureus;
(4) MIC at 50 µg/mL against C. albicans and
100 µg/mL against all bacteria tested.
[156]
C. erythrophyllum
(leaf)
Apigenin, genkwanin,
5-hydroxy-7,4′ -dimethoxyflavone,
rhamnocitrin, kaempferol,
quercetin-5,3′ -dimethylether, and
rhamnazin
MIC values in the range of 25–50 µg/mL against
Vibrio cholerae and Enterococcus faecalis;
rhamnocitrin and quercetin-5,3′ -dimethylether
inhibited Micrococcus luteus and Shigella sonnei at
an MIC of 25 µg/mL.
[60]
C. hartmannianum
(root)
Luteolin and quercetin
3-O-galactoside-7-O-rhamnoside
–(2→1)-O-D-arabinopyranoside
Luteolin showed a growth-inhibitory effect against
M. smegmatis (with an MIC of 250 µg/mL)
[76]
[156]
Stilbenes
C. apiculatum
(leaves)
5-hydroxy-3,4′ -dimethoxybibenzyl;
4′ - hydroxy-3,4,5-trimethoxybibenzyl; 4′ ,
5-dihydroxy-3,4-dimethoxybibenzyl, and
4,4′ -dihydroxy-3,5-dimethoxybibenzyl
5-hydroxy-3,4′ -dimethoxybibenzyl was active against C. albicans,
Proteus vulgaris and S. aureus with an MIC of
25–50 µg/mL.
4′ -hydroxy-3,4,5-trimethoxybibenzyl was active against C. albicans with an MIC
of 50 µg/mL.
C. caffrum
(branches, leaves and fruits
used in a combination extract)
Combretastatin
Combretastatin caused astrocyte reversal and
inhibited the murine P388 lymphocytic leukemia
cell line. No antimicrobial tests.
[157]
C. caffrum
(stem wood)
The cis-stilbenes, combretastatin A-2
(CA-2), combretastatin A-3 (CA-3), and
the trans-stilbene, combretatastatin B-2
Combretastatins A-2 and A-3 inhibited markedly
the polymerization of tubulin in P388 lymphocytic
leucemial cells. No antimicrobial tests.
[158]
C. caffrum
(stem wood)
The cis-stilbene, combretastatin A-1
(CA-1), was isolated for the first time, and
combretastatin B-1 was obtained by
selective hydrogenation of CA-1.
Combretastatins A-1 and B-1 inhibited
microtubule assembly in vitro and where potent
inhibitors of the binding of colchisin to tubulin. No
antimicrobial tests.
[159]
C. caffrum
(stem wood)
The unusual macrocyclic lactone,
combretastatin D-1, was isolated from a
species of Combretum for the first time.
Combretastatin D-1 showed PS (P388 lymphocytic
leukemia), cell-line inhibitory activity at ED50
3.3 µg/mL. No antimicrobial tests.
[160]
C. caffrum
Combretastatin B-3 and B-4
PS leukemia ED50 values of 0.4 and 1.7 µg/mL,
respectively. No antimicrobial tests.
[161]
C. caffrum
(stem wood)
Combretastatin A-4, A-5 and A-6
Growth-inhibitory effect against Neisseria
gonorrheae:
CA-4 and CA-5: MIC between 25 and 50 µg/mL,
CA-6: MIC between 50 and 100 µg/mL.
[162]
C. kraussii
(root)
Combretastatin A-1 and B-1 and their
corresponding 2-O-β-D-glucosides
Growth-inhibitory effect against mouse
lymphocytic leukemia cells. No antimicrobial tests.
[163]
C. psidioides
(stem bark)
Combretastatin B-2 and its
dihydrostilbene derivatives were present
in a methanol extract of C. psidioides
stem bark.
MIC not tested for CB-2, but MIC for the MeOH
extract of the stem bark of C. psidioides against
M. smegmatis was 625 µg/mL.
[23]
C. woodii
(leaf)
2′ ,3′ ,4-trihydroxyl-3,5,4′ trimethoxybibenzyl
(combretastatin B-5)
MIC between 16 and >250 µg/mL against S. aureus,
E. coli, P. aeruginosa, and E. faecalis.
[145]
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Table 5. Cont.
Species
Compounds
Antimicrobial Activity
References
Phenantrenes
C. adenogonium (root)
Substituted phenanthrenes
Compounds were active against P. aeruginosa with
an MIC of 160 µg/mL.
[164]
C. apiculatum
(heartwood)
Five substituted
9,10-dihydrophenanenthrenes and four
phenanthrenes
Three phenanthenes totally inhibited the growth of
Penicillium expansum at 20 µg/mL in a
bioautographic analysis.
[165]
C. collinum
(leaf)
9,10-dihydro-3,6,7-trimethoxy-2,5phenanthrenediol
Active against M. fortuitum and S. aureus with an
MIC of 25 µg/mL.
[156]
Compounds 1, 2, and 3 showed some activity
against M. fortuitum and S. aureus with an MIC of
25 µg/mL.
[156]
No biological activity tests.
[166]
No tests.
[167]
C. hereroense (fruit)
C. molle (heartwood)
(1) 5,7-dimethoxy-1,2,3-phenanthrenetriol
(2) 5,7-dimethoxy-2,3-phenanthrenediol
(3) 9,10-dihydro-3,5-dimethoxy-2,7phenanthrenediol
(4) 3,5,7-trimethoxy-2,6-phenanthrenediol
Fourteen 1,9- dihydrophenanthrenes and
three phenolic bibenzyls
Cyclobutanes
C. albopunctatum
(aerial parts)
Two novel cyclobutane chalcone dimers
Alkaloids
C. dolichopetalum
(root)
Echinulin and arestrictin B (indole
containing diketopiperazine alkaloids)
No tests.
[34]
C. micranthum
Piperidine-flavan alkaloids from
n-butanol extracts of the leaves: Kinkeloid
A1, A2, B1, B2, C1, C2, D1, and D2
No tests.
[27,45]
Abbreviations: MIC—minimum inhibitory concentration; CA-1—combretastatin A-1; CA-2—combretastatin A-2;
CA-3—combretastatin A-3; CA-4—combretastatin A-4; CA-5—combretastatin A-5; CA-6—combretastatin A-6;
CB-1—combretastatin B-1; CB-2—combretastatin B-2; CB-3—combretastatin B-3; CB-4—combretastatin B-4; CB5—combretastatin B-5; CD-1—combretastatin D-1; and ED50 —effective dose resulting in 50% growth inhibition.
5.1. Phytochemistry and Antimicrobial Compounds of Combretum Species
Of the species of the genus Combretum (approximately 250 species), only thirty-one
(31) species have been studied for their phytochemistry [15]. To date, at least 261 compounds, mainly terpenoids (of which the majority are triterpenes) and phenolic compounds
(phenolic acids, diarylpropanes, tannins, flavonoids, stilbenoids, and phenanthrenes), have
been isolated from Combretum species (Table 5). Simple triterpenoids and triterpenoid
glycosides, as well as stilbenoids (such as combretastatins), are common in the genus
Combretum [15]. Some of them, such as combretastatins B-5 and B-1 and their glycosides,
as well as hydroxyimberbic acid, have shown potent antibacterial effects, with MIC values as low as 1.56–3.9 µg/mL [147]. In general, cycloartane, lupane, ursane, oleanane,
and dammarane-type triterpenes are well-known in the Combretum species [15,68,168].
Other compounds include lignans, amino acids (non-protein), lipids, and steroids [15,28].
Moreover, though not widely found, some alkaloids have been identified in Combretum
species [45]. An alkaloid extract of C. zeyheri showed efflux-pump inhibitory activity,
although the active compounds were not characterized [135]. In addition, hydrolysable
tannins, including ellagi- and gallotannins and condensed tannins (proanthocyanidins),
have been characterized in African Combretum species [23].
5.1.1. Triterpenes and Saponins
Triterpenes are involved in the antimicrobial defence system of many plants, and
Combretum spp. accumulate them especially in the secretory glands (trichomes) of their
leaves [169]. At least ten African species of Combretum, with a common occurrence in
southern Africa and reputed uses for bacterial and fungal infections in traditional medicine,
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were studied for their antimicrobial triterpenes and triterpenoid glycosides (saponins)
(Table 5). The species that have been studied most frequently are C. imberbe and C. padoides
(syn. C. minutiflorum Exell). Moreover, C. erythrophyllum, C. racemosum, C. vendae, C. zeyheri,
C. collinum, C. molle, and C. laxum were also studied in this respect [149–151]. Leaf material
was used in most studies, but roots (C. racemosum) and stems (C. laxum) have also been
used. As not only the leaves, but also the roots and stems of Combretum spp. are used for
the preparation of herbal remedies for the treatment of infections, these parts of Combretum
spp. should also be investigated for their triterpenes.
Hydroxylated pentacyclic olean-12-ene triterpene saponins, as well as the triterpenoid
aglycones, hydroxyimberbic acid, and imberbic acid, were isolated from the leaves of
C. imberbe (Figure 4). The rhamnose-containing saponins inhibited the growth of a number
of Gram-positive bacteria but were less active than imberbic acid [147]. Imberbic acid
showed the lowest MIC values of 1.56 and 3.13 µg/mL against Mycobacterium fortuitum
and S. aureus, respectively. However, all saponins and the imberbic acid were less active
against E. coli, with MIC values above 100 µg/mL
β [147]. Mollic acid and its glucosides,
including mollic acid–β-D-glucoside, -arabinoside and -xyloside, as well as imberbic acid,
were characterized from the leaf trichomes of C. molle and C. petrophilum [148,169]. However, according to our literature review, mollic acid and its glucosides have not been tested
for their antimicrobial effects; they are foremost known for their good molluscididal effects [169]. Dawe et al. [168] found two new cycloartane-type triterpenes, combretins A and
B, from the leaves of Combretum fragrans (syn. C. adenogonium). Angeh et al. [26] isolated
a new antibacterial oleanane-type triterpenoid glycoside from a dichloromethane
α extract
β
of the leaves of C. padoides, namely 1α,
β 23β-dihydroxy-12-oleanen-29-oic-acid-23β-O-α-4α
acetylrhamnopyranoside and 1,22-di-hydroxy-12-oleanen-30-oic acid. Both compounds
showed activity against S. aureus and E. coli (with an MIC of 63 µg/mL for both compounds).
The pentacyclic triterpene olean-12-ene-3-one, isolated from the leaves of C. collinum, was
mildly antibacterial against S. aureus and E. coli (with an MIC of 568.9 µg/mL) [146].
(A)
(B)
Figure 4. (A) The pentacyclic triterpene, imberbic acid, and (B) 23-hydroxyimberbic acid 23-O-α-L3,4-diacetylrhamnopyranoside, a triterpene saponine. Both compounds were isolated from C. imberbe
leaves [147]. Source: ChemDraw, SciFinder 2022.
5.1.2. Flavonoids
A number of African Combretum species have been investigated for their flavonoids
and/or the antimicrobial effects of isolated flavonoids (Table 5). Among the most studied
African species regarding flavonoids are C. micranthum, C. apiculatum, and C. erythrophyllum. Various methoxylated and hydroxylated flavonoid derivatives, including quercetin
derivatives, are common within the genus Combretum [170]. Flavonoids from African
α
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Combretum species have been found to inhibit the growth of bacteria and fungi and, in
addition, some flavonoids were found to affect the quorum-sensing system of bacteria. For
example, Vandeputte et al. [119] found that C. albopunctatum, a species indigenous to Madagascar, contains catechins that inhibited the transcription of quorum-sensing (QS) factor
regulation genes in P. aeruginosa. Moreover, in a later study, Vandeputte et al. [171] found
that naringenin, eriodictyol, and taxifolin, also isolated from C. albopunctatum, significantly
reduced the QS-dependent production of pyocyanin and elastase in P. aeruginosa, without
affecting its growth.
′ methoxylated quercetin derivatives rhamnocitrin, rhamnazin, and ′
Kaempferol and the
quercetin-5,3′ -dimethylether, as well as genkwanin, apigenin, and hydroxy-4′ ,7
-dimethoxyflavone, were characterized from an acetone leaf extract of C. erythrophyllum [60].
All the compounds were active against Vibrio cholerae and Enterococcus faecalis (with MICs
′
of 25–50 µg/mL).
′
′
′
Katerere et al. [156] characterized two simple chalcones, cardamomin and 4 -hydroxy2′ ,6′ -dimethoxychalcone, from the leaves of C. apiculatum. The antibacterial effects of both
compounds were moderate to weak (with MIC values 50–100 µg/mL), with S. aureus
being more sensitive than M. fortuitum and E. coli. Additionally, both chalcones inhibited
C. albicans with an MIC of 50 µg/mL. In addition, pinocembrin, alpinetin, and chrysin were
characterized from the leaf extract of C. apiculatum. Pinocembrin showed strong growth inhibition against C. albicans, with an MIC of 6.25 µg/mL (compared to an MIC of 12.5 µg/mL
for fluconazole) and good activity against S. aureus (with an MIC of 12.5 µg/mL). These
MIC values were hitherto the lowest reported regarding flavonoids in African Combretum
species. Katerere et al. [155] presented follow-up results on flavonoids in C. apiculatum
leaves and isolated three antibacterial flavonoids: the phytoalexins flavokawain A, a
chalcone originally found in Piper methystichum (Kava), and alpinetin and pinocembrin
(Figure 5). S. aureus was the most sensitive bacterium and was inhibited at an MIC of
40 µg/mL by flavokawain A and alpinetin. However, pinocembrin demonstrated an MIC
of 80 µg/mL against S. aureus; this contrasted with the MIC of 12.5 µg/mL that was established in the previous investigation by Katerere et al. [156]. E. faecalis was inhibited at an
MIC of 40 µg/mL by alpinetin and pinocembrin. Pinocembrin and alpinetin inhibited Pseudomonas aeruginosa at an MIC of 40 µg/mL. Salih et al. [76] found that luteolin, which was
present in a root ethyl acetate extract of C. hartmannianum, inhibited the growth of M. smegmatis at an MIC of 250 µg/mL. Moreover, in this same investigation, Salih et al. [76] found
→quercetin-3-O-galactoside-7-O-rhamnoside-(2
β
that also
→1)-O-β-D-arabinopyranoside was
present in the antimycobacterial root extract of C. hartmannianum.
(A)
(B)
(C)
Figure 5. Structures of three antibacterial flavonoids known from African Combretum: (A) flavokawain
A, (B) pinocembrin, and (C) alpinetin. ChemDraw, SciFinder 2022.
5.1.3. Hydrolysable Tannins, Their Derivatives, and Condensed Tannins
Although hydrolyzable tannins (HT) such as gallotannins (GT), ellagitannins (ET) and
their derivatives (ellagic acid and gallic acid derivatives) are common in Combretum spp.,
only seven species have hitherto been studied in depth regarding these compounds [15,172]
(Table 5). This could be because most ETs that have been studied for their antimicrobial
effects to date have shown moderate or mild in vitro growth inhibitory effects (with MIC
values mostly around 25–1000 µg/mL, with some exceptions), and their bioavailability is
poor when used in oral medications. Interestingly, however, ETs were found to potentiate
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the effects of antibiotics [173] and could have great potential especially in topical applications. In their review, Buzzini et al. [174] pointed out that, although the antimicrobial effects
of hydrolysable tannins are well studied, most studies have not evaluated this activity.
Polyphenols, and especially ellagitannins, are not well studied in Combretum spp. [15,172].
The molecular structures of some ellagitannins found in Combretum spp. are presented in
Figure 6. Other genera and species, especially Terminalia spp. (Combretaceae), Punica granatum
(Lythraceae), and Eucalyptus spp. (Myrtaceae)—all of which belong to the order Myrtales,
which is rich in ETs—have been studied more thoroughly for their ellagitannins. Some of
the ellagitannins found in these genera are also found in some Combretum spp., such as
punicalagin and the ellagitannin monomer, 2,3-S-hexahydroxydiphenoyl-D-glucose, the
characteristic component of many ETs [175–177]. Jossang et al. [176] were among the first
to study ellagitannins in Combretum in 1994. They found that water decoctions of the leaves
of Combretum glutinosum contained punicalin, punicalagin, 2,3-S-hexahydroxydiphenoylD-glucose, and combreglutinin. The ellagitannins were not tested for their antimicrobial
effects in this study.
(A)
(B)
(C)
(D)
Figure 6. Ellagitannins in African Combretum spp. (A) castalagin, (B) terchebulin, (C) punicalagin,
and (D) corilagin. ChemDraw, SciFinder 2022.
The extracts of many African Combretum spp. are also rich in proanthocyanidins
(condensed tannins) and related polyphenols, such as epigallocatechin and catechin [23,178].
Tannins were found to be useful for the prevention of food spoilage and especially for
topical applications, such as for the treatment of skin infections and wounds, as well as for
mouthwashes and in toothpastes via their antimicrobial and antioxidative effects [122,179].
Moreover, tannins reduced the growth of pathogenic clostridia, but did not affect the
probiotic lactobacilli and bifidobacteria in the gut [180]. In African countries, traditional
medicinal preparations from Combretum spp., such as decoctions and macerations, are
used both topically and orally for the treatment of infections. These preparations have
been shown to be rich in hydrolyzable tannins, and especially ellagitannins, which could
explain the antibacterial and antifungal potency of these species [23,65]. Thus, African
Combretum species could be potential sources of tannin-enriched extracts and tannins for
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food safety and for the treatment of topical and oral infections, as well as for balancing
the microbial flora in the gut. Some studies on tannins and their derivatives in African
species of Combretum and their in vitro antimicrobial effects are discussed below, and more
are listed in Table 5.
In two antibiotic assays, including a growth-inhibition assay in broth and a singlecell infection antibiotic assay using Mycobacterium marinum as test bacterium and Acanthamoeba castellanii as host, Diop et al. [65] found that α- and β-punicalagin, isolated from
a decoction of Combretum aculeatum, possessed an IC50 value of 51.48 µM, compared to
6.99 µM for rifampicin. As α- and β-punicalagin are not bioavailable, Diop et al. [65] also
studied the antibacterial effects of urolithins, the metabolites resulting from the metabolic
degradation of α- and β-punicalagin, and found that urolithins A, B, and D provided
weak growth-inhibitory effects against Mycobacterium marinum. However, due to the high
content of tannins in the decoction of C. aculeatum for the treatment of TB, Diop et al. [65]
suggested that the levels of urolithins might reach plasma concentrations that would be
relevant for in vivo antimycobacterial effects. Thus, Diop et al. [65] concluded that their
results could justify the use of C. aculeatum decoctions for the treatment of TB in Senegalese
traditional medicine, and that the anti-TB effects of these decoctions are related to their
ellagitannins and particularly to punicalagin and its urolithin metabolites. In contrast to
Diop et al. [65], Asres et al. [111] showed that punicalagin, isolated from the stem bark
of Combretum molle, possessed only weak growth-inhibitory effects against M. tuberculosis
typus humanus ATCC 27294, although the growth inhibition was total at concentrations
higher than 600 µg/mL. Thus, different species and strains of Mycobacterium may differ
in their sensitivity to ellagitannins. Some authors have, however, chosen to study the
content of ETs and their related derivatives (ellagic acid derivatives) in Combretum extracts
with good antibacterial activity. For example, Fyhrquist et al. [23] showed that a methanol
extract of the stem bark of C. psidioides, which demonstrated a good growth-inhibitory effect
against Mycobacterium smegmatis (MIC 625 µg/mL), contained corilagin, sanguiin-H4, and
punicalagin (Figure 6), along with thirteen unknown ellagitannins and methyl ellagic acid
xyloside as the main component. In this same investigation, ellagitannin and ellagic acid
(EA) derivative-rich extracts of C. zeyheri and C. padoides were also found to provide growth
inhibitory effects against M. smegmatis. In addition, methyl ellagic acid, dimethyl-ellagic
acid, and dimethyl-galloyl ellagic acid were characterized in Combretum zeyheri, and ellagic
acid arabinoside and methyl ellagic acid xyloside were present in C. padoides [23]. Previously, it was demonstrated that ellagic acid derivatives have antimycobacterial potential.
Ellagic acid derivatives isolated from the stem bark of Terminalia superba, such as 3,4′ -diO-methyl-ellagic acid-3′ -O-β-D-xylopyranoside and 4′ -O-galloyl-3,3′ -di-O-methyl-ellagic
acid -4-O-β-D-xylopyranoside, were strongly active against Mycobacterium smegmatis and
M. tuberculosis, with MIC values between 4.88 and 9.76 µg/mL [181]. However, Fyhrquist
et al. [23] found that ellagic acid itself was not very active against M. smegmatis, with
an MIC of 500 µg/mL, and therefore the methylations and glycosylations of EA seem to
be important for its antimycobacterial activity. Moreover, Fyhrquist et al. [23] tested the
growth inhibitory effect of corilagin against M. smegmatis to assess the contribution of ETs
to the antimycobacterial effects of the Combretum extracts. Corilagin gave only a weak
antimycobacterial effect (an MIC of 1000 µg/mL). Therefore, it was suggested that the
ellagitannins act in concert with each other as well as with other compounds present in the
active extracts. However, Fyhrquist et al. [23] pointed out that other, unidentified ETs in
the Combretum extracts should be quantified (proportion of the extract), isolated and tested
to assess the final contribution of the ETs to the antimycobacterial effects of the extracts. In
some other studies, corilagin revealed a good antibacterial effect against S. aureus, having
an MIC value of 25 µg/mL, and inhibited the growth of methicillin-resistant S. aureus
(MRSA) [182,183]. In addition, corilagin showed potentiating effects in combination with
various β-lactam antibiotics, reducing their MIC values against MRSA [181]. Interestingly,
it was found that corilagin reduced the synthesis of penicillin-binding protein 2a, thus
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decreasing the resistance of MRSA to β-lactam antibiotics [183,184]. Thus, corilagin could
be effective against skin infections and wounds caused by S. aureus.
Wood and bark extracts of Combretum hartmannianum are used in the treatment of
bacterial infections. Thus, Mohieldin et al. [122] studied the effects of a methanol extract
of the stem bark of C. hartmannianum on Porphyromonas gingvinalis, a bacterium causing
periodontal diseases. The extract resulted in both growth inhibition (with an MIC of
0.5 mg/mL) as well as in metalloproteinase 9 (MMP-9) inhibition. Moreover, the terchebulin
that was found in the extract inhibited MMP-9 significantly, although its growth-inhibitory
effects against P. gingvinalis were moderate (MIC 500 µg/mL). Another ET in the extract,
flavogallonic acid dilactone, provided an MIC of 1000 µg/mL against P. gingvinalis. In
summary, regarding punicalagin, terchebulin, and flavogallonic acid dilactone, it was found
that all compounds inhibited the growth of Helicobacter pylorii and Propionibacter acne, with
MIC values ranging from 125 to 250 µg/mL [78].
Salih et al. [76] found that methanol Soxhlet and ethyl acetate extracts of the root
of C. hartmannianum provided growth-inhibitory effects against Mycobacterium smegmatis. These effects were partly attributed to ellagitannins and ellagic acid derivatives since
these compounds were the main components in the extracts. Fifty-four polyphenols were
characterized in the ethyl acetate extract. Among them were gallic acid, terflavin B and
its two isomers, castalagin, corilagin, tellimagrandin I and its derivative, (S)-flavogallonic
acid dilactone, punicalagin, epigallocatechin gallate (EGCG), and methyl-ellagic acid xylopyranoside (Figure 6). However, when tested alone, corilagin, gallic acid, and ellagic
acid demonstrated high MIC values against M. smegmatis in this study (500–1000 µg/mL).
Castalagin, which was present in the root of C. hartmannianum [76], was found to inhibit the
growth of E. coli [185–187] as well as Vibrio strains and Aeromonas sobria [154]. Moreover,
tellimagrandin I, also found in the C. hartmannianum root [76], inhibited S. aureus, E. coli
and Clostridiales perfringens [186]. In addition, tellimagrandin I was reported to markedly
reduce the MIC of β-lactam antibiotics in MRSA via its ability to decrease the synthesis
of penicillin-binding protein 2a [183]. To date, however, no studies exist on the effects of
castalagin, tellimagrandin I, or (S)-flavogallonic acid on mycobacteria.
Epigallocatechin gallate (EGCG) that Fyhrquist et al. [23] found in a butanol extract of
the stem bark of C. psidioides showed antibacterial activity against both Gram-negative and
Gram-positive bacteria, among them Aeromonas and Vibrio strains [154]. Moreover, EGCG
affects the cell-wall integrity of M. smegmatis mc 2155 [153].
A large number of oligomeric procyanidines were found from a leaf extract of C. mucronata,
but the antimicrobial effects of these condensed tannins were not investigated. However,
the procyanidines were found to possess anthelminthic effects [152].
5.1.4. Stilbenoids (Bibenzyles and Phenanthrenes)
Bibenzyles and their derivatives are rare in higher plants. However, they are common
within the genus Combretum; some of these compounds are listed in Table 5. In Combretum
spp., cis-stilbenes (Combretastatins A), dihydrostilbenes (Combretastatins B), phenanthrenes (Combretastatins C, formed via phenolic oxidation of bibenzyls), and macrocyclic
lactones (Combretastatins D) have been characterized [188]. Pure combretastatin was the
first bibenzyl to be isolated from the fruits, stems, and barks of the South African tree
C. caffrum [157]. Soon after, combretastatins A-2, A-3, and B-2 (CA-2, CA-3, and CB-2) were
isolated from the stem wood of C. caffrum [158], and shortly after that, combretastatin A-1
and combretastatin B-1 (CA-1 and CB-1) were isolated [159]. Moreover, in 1988, the unusual
combretastatin D-1, containing two additional rings (when compared to the A- and B-series
combretastatins) and a lactone ring, was isolated from the stem wood of C. caffrum [160]. Additionally, the B-series combretastatins, combretastatin B-3 and B-4 (CB-3 and CB-4), were
characterized from C. caffrum stem wood in 1988 [161]. In 1995, the most important bibenzyl
compounds (with respect to their anti-cancer potential), namely, combretastatins A-4 (CA4), A-5 (CA-5), and A-6 (CA-6), were characterized from the stem wood of C. caffrum [162].
Later, combretastatin A-4 (CA-4) was identified from C. microphyllum [189]. Addition-
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ally, combretastatin A-1, combretastatin B-1, and the corresponding 2-O-β-D-glucosides
of the two combretastatins were identified from the root of C. kraussii [163] (Figure 7).
Several stilbenoids were isolated from the wood of C. erythrophyllum: combretastatin A-1,
(-)-combretastatin, combretastatin A-1-2-β-D-glucoside, and combretastatin B-1- 2-β-Dglucoside [190]. From the aerial parts of C. molle, 3,4′ -dihydroxy-4,5-dimethoxybibenzyl
and seven 1,9-dihydrophenantherens were characterized [166]. Stilbenes have also been
characterized from C. psidioides, including fourteen 9,10-dihydrophenanthrenes and three
bibenzyls (among them 4′ -hydroxy-3,4,5-trimethoxybibenzyl) from the heartwood [191], as
well as combretastatin B-2 from the stem bark [23].
(A)
(B)
(C)
(D)
Figure 7. Stilbenes in Combretum spp. (A) combretastatin A-1, (B) combretastatin B-1, (C) combretastatin A-4, and (D) combretastatin B-5. ChemDraw, SciFinder 2022.
Combretastatins are mainly known for their significant in vitro and in vivo anti-cancer
effects via their inhibitory effects of tubulin polymerization and the disruption of tumor
vasculature formation [192]. In this respect, combretastatin A-4 and A-1 specifically have
been found to be some of the most potent, natural anti-tubulin compounds [192]. However,
less is known regarding the antimicrobial potential of the combretastatins and phenanthrenes from Combretum species. Some of the combretastatins in Combretum spp. possess
antibacterial effects. For example, combretastatin B-5, isolated from C. woodii, showed
significant antibacterial activity against Staphylococcus aureus (with an MIC of 16 µg/mL)
and lower activity against Pseudomonas aeruginosa and Enterococcus faecalis (with MIC values
of 125 µg/mL) [13,145]. Combretastatins A-4 and A-5, isolated from Combretum caffrum
stem wood, inhibited the growth of Neisseria gonorrheae, with MIC values ranging from
25 to 50 µg/mL [162]. Katerere et al. [156] found four phenanthrenes in a fruit extract of
C. hereroense as well as one phenanthrene and two bibenzyls, including combretastatin, in a
leaf extract of C. collinum. The phenantherenes were active against Mycobacterium fortuitum
and S. aureus (with MIC values of 25 µg/mL), and apiculatol (a bibenzyl) was active against
C. albicans and S. aureus (with MIC values of 25 µg/mL). Mushi et al. [164] isolated three substituted phenanthrenes from the root of C. adenogonium, of which all had significant growth
inhibitory activity against P. aeruginosa. Malan & Swinny [165] isolated five substituted
9,10-dihydrophenanenthrenes and four phenanthrenes from the heartwood of C. apiculatum;
three phenanthrenes provided complete growth inhibition against Penicillium expansum in
a bioautography assay.
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5.1.5. Cyclobutanes
Katerere et al. [167] isolated two novel cyclobutane chalcone dimers from a dichloromethane
extract of the aerial parts of C. albopunctatum. The compounds were not tested for their
antimicrobial activities. However, heteroaryl chalcones containing a cyclobutane ring
structure are known to possess antimicrobial effects [193].
5.1.6. Alkaloids
Only few alkaloids are known from Combretum spp. The pyrrolidine alkaloid, combretine, and the piperidine alkaloid betonicine have been isolated from the leaves of
C. micranthum. In two different studies, a large number of piperidine-flavan alkaloids—the
kinkeloids, with a completely new basic molecular structure consisting of a piperidine
unit attached to the 6- or 8-carbon of the flavan backbone—were found in leaf extracts of
C. micranthum (Figure 8) [27,45,194]. Kinkeloids of the A-, B-, C-, and D-series were characterized. Piperidine-flavan alkaloids are not known from other plants. The combination of a
flavan unit with a piperidine alkaloid can make flavan-piperidine alkaloids particularly
biologically active [194]. According to a qualitatitive screening of the alkaloids in a leaf
extract of C. dolichpetalum, the extract contained quinolone, isoquinoline, tropane, purine,
and indole alkaloids [195]. However, the molecular structures of these alkaloids were not
further characterized.
(A)
(B)
Figure 8. Piperidine-flavan alkaloids (kinkéloid- alkaloids) characterized from Combretum micranthum [45]: (A) kinkeloid A1 and (B) kinkeloid A2. ChemDraw, SciFinder 2022.
5.2. Phytochemistry and Antimicrobial Compounds of Pteleopsis Species
GC-MS analyses of an aqueous extract of the stem bark of P. suberosa showed that
the stem bark contained, inter alia, the following compounds: arjunglucoside (67.36%),
taxifoline (7.42%), luteolin (4.88%), reserpine (3.72%), furoquinoline (3.51%), berberine
(3.02%,), ursolate (2.23%), and cryptolepine (2.00%) [96]. De Leo et al. [95] isolated thirteen triterpenoids from chloroform, methanol and n-butanol extracts of the stem bark of
P. suberosa, four of which were new triterpenoid glycosides. Moreover, the triterpenoids
were tested for their anti-Helicobacter activities since P. suberosa stem bark decoctions are
used in Malian traditional medicine for the treatment of ulcers. Additionally, a methanol
extract of the stem bark had shown anti-Helicobacter effects in a previous investigation [142].
Arjunglucoside I was the only active triterpenoid among the thirteen tested. It significantly
inhibited three metronidazole-resistant strains of H. pylori, with MIC values ranging from
1.9 to 7.8 µg/mL, the effects being comparable to clarithromycin and much more effective
than metronidazole [95].
Pteleopsoside (syn. bellericagenin {B 3-O-[β-D-glucopyranosyl-(1→2)-α-D-glucopyranoside],
a new saponin with two D-glucose units, and two sphingolipids, hylodendroside-II and
I, were isolated from the stem bark of Pteleopsis hylodendron. In addition, 2α, 3β, 23triacetoxy-19α-hydroxyolean-12-en-28-oic acid, friedelin, lupeol, β-carotene, sitosterol,
and stigmasterol were characterized [196]. Sphingolipids were found to protect the liver
from toxic compounds and to have antitumor, antimicrobial, and immunostimulatory
effects [197,198].
Ngounou et al. [90] isolated two new saponins (2α, 3α, 19α, 23-tetrahydroxyolean-12en-28-O-β-D-galactoside and a triterpenoid (2α, 3β, 21β, 23-tetrahydroxyolean-12-en-28-
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oic acid) from the stem bark of P. hylodendron. The structures of these compounds were
elucidated by spectroscopic studies.
Fractions containing anthraquinones, alkaloids, and anthocyanins were isolated from
a methanol extract of the stem bark of P. hylodendron. Two of these fractions inhibited the
growth of E. coli, Proteus mirabilis, Salmonella paratyphi B, Enterococcus faecalis, and S. aureus
with an MIC of 0.97 µg/mL, compared to MIC values of 781–12,500 µg/mL for the crude
methanol extract [139]. In contrast, all the fractions containing only alkaloids were devoid
of activity.
6. Potentiating Effects
In African traditional medicine, herbal decoctions and other preparations commonly
consist of a combination of two or more medicinal plants [36,199,200]. Moreover, in
traditional, small-scale farming in African countries, combinations of plants are also used
as extracts for crop-plant protection [201,202]. The various phytochemicals in the extracts
can enhance the antimicrobial effects of each other and lead to synergistic and/or additive
effects [203]. It has been demonstrated that plant extracts and plant-derived compounds
can act synergistically and/or additively with conventional antimicrobial drugs [7]. Using
plant-derived compounds/extracts as antibiotic adjuvants could be a means of reducing
the required doses of antibiotics, thus reducing their adverse health effects and at the same
time restoring the potency of antibiotics that have lost their effects against resistant strains
of bacteria and fungi. Plant extracts and their compounds could be used as antibiotic
adjuvants, especially against multi-resistant bacteria and fungi. The interest in the potential
of plant extracts and plant-derived compounds as antibiotic adjuvants is a growing research
field and was recently proposed by many researchers [204]. However, not all extracts
and compound combinations result in synergistic effects, and it is therefore important
to calculate the fractional inhibitory concentration index (FICI) that defines the nature
of the combination effect (synergistic, additive, indifferent, or antagonistic) [19]. For the
genus Pteleopsis, our literature search resulted in no findings on combination studies with
antibiotics or with extracts of other medicinal plants.
6.1. Combination Effects of Combretum Species with Antibiotics and Other Plant Extracts
To date, a small number of studies have been performed on the interactions of extracts
of the African Combretum species with conventional antimicrobials (antibiotic-resistance
modifying effects) and/or with other plant species. Most of these interaction studies
were performed using microdilution methods, and some studies included a checkerboard
method. Agar diffusion was used as a screening method in some studies. In most of
the screenings, the plant extracts and antibiotic combinations, as well as the extracts’
combinations, displayed synergistic effects.
Table 6 summarizes the results reported in the literature on the combination effects
of extracts of Combretum species with of antibiotics and with extracts of other medicinal
plants on bacterial and fungal growth. For example, C. edwardsii and C. kraussii have been
studied in this respect. They were found to produce strong synergistic effects with many
antibiotics, including the third-generation cephalosporine and cefotaxime. Drug-resistant
S. aureus was especially sensitive, whereas drug-resistant E. coli and K. pneumoniae showed
more resistance [30]. Interestingly, none of the combinations were found to be antagonistic.
Additionally, a water extract of C. kraussii in combination with penicillin showed especially
good growth inhibition against S. aureus with a FICI value of 0.04, indicating a strong
synergistic effect [30].
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Table 6. Antibiotic and extract potentiating effects in two-component combinations. Reported
interactions of Combretum species with antimicrobials and with extracts of other plants.
Species, Extracts and Antibiotics Combinations
Screening Method and Antibiotic Potentiating Effect;
FICI, Reduction of MIC
Reference
Combretum edwardsii
Hexane, dichloromethane, and ethyl acetate
fractions of Combretum edwardsii leaves +
cefotaxime, ampicillin, chloramphenicol, penicillin
and amoxicillin
Checkerboard method:
Drug-resistant E. coli: Synergistic effect of a hexane
fraction and cefotaxime. FICI value of 0.07.
Multidrug resistant Klebsiella pneumoniae: Synergistic
effects of hexane, dichloromethane, and ethyl acetate
fractions with cefotaxime. FICI values between 0.03 and
0.12. A combination of the ethyl acetate extract and
cefotaxime provided the strongest synergistic effects with an
FICI value of 0.03.
Penicillin-resistant Staphylococcus aureus: Synergistic
effects of hexane, dichloromethane, and ethyl acetate
fractions in combination with ampicillin, chlorampenicol,
penicillin, and amoxicillin. FICI values between 0.05 and
0.37. The most effective combination was that of a hexane
extract and amoxicillin, showing an FICI value of 0.05.
[30]
Combretum kraussii
Hexane, dichloromethane, ethyl acetate, and water
fractions of Combretum kraussii leaves + cefotaxime,
ampicillin, chloramphenicol, penicillin
and amoxicillin
Checkerboard method:
Drug-resistant E. coli: Synergistic effects of
dichloromethane and ethyl acetate extracts in combination
with cefotaxime. FICI values of 0.07 and 0.064, respectively.
The most effective combination was that of an ethyl acetate
extract and cefotaxime.
Multidrug resistant Klebsiella pneumoniae: Synergistic
effects of hexane, dichloromethane, ethyl acetate, and water
fractions in combination with cefotaxime. FICI values of
0.062–0.38. The most effective combination was that of a
hexane extract and cefotaxime.
Penicillin resistant Staphylococcus aureus: Synergistic
effects of hexane, dichloromethane, ethyl acetate, and water
extracts in combination with ampicillin, amoxicillin,
chloramhenicol, and penicillin. FICI values between
0.04–0.38. The most effective combination was a water
extract and penicillin.
[30]
Combretum hereroense, Citrus lemon, and
Apodytes dimidiata
Hexane, dichloromethane, acetone, and methanol
extracts of the leaves in two-species
extract combinations
Serial microdilution method:
The MICs of the crude extracts against Mycobacterium
smegmatis ranged between 0.1 mg/mL (dichloromethane
extract of Apodytes dimidiata) and 3 mg/mL (hexane extract
of Citrus lemon). The MICs of the C. hereroense crude extracts
ranged between 0.6 and 1.6 mg/mL, with the acetone and
dichloromethane extracts being the most growth inhibitory.
The best combinations; Combretum hereroense with
Apodytes dimidiata, hexane and acetone, and
dichloromethane and methanol; resulted in MIC values of
0.04 mg/mL and showed synergistic effects.
[31]
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Table 6. Cont.
Species, Extracts and Antibiotics Combinations
Screening Method and Antibiotic Potentiating Effect;
FICI, Reduction of MIC
Reference
Combretum erythrophyllum, Combretum molle,
Harpephyllum caffrum, Quercus acutissima, and
Solanum mauritianum
Water, ethyl acetate, and acetone extracts of the
leaves in two-species extract combinations
Microplate dilution assay and FIC-index calculation:
MIC values of 0.04– > 2.5 mg/mL of the crude extracts of
C. erythrophyllum against the tested Fusarium spp., with the
strongest effects shown by the acetone and ethyl acetate
extracts (MIC values of 0.04–0.08 mg/mL). Strong
synergistic effects of the acetone extract of C. erythrophyllum
in combination with acetone extracts of Harpephyllum
caffrum, Quercus acutissima, and Solanum mauritianum
against Fusarium proliferatum and F. verticillioides (MIC
valuess of 0.002–0.001 mg/mL).
MIC 0.04– > 2.5 mg/mL of the crude extracts of C. molle
against the Fusarium spp. All tested extracts, including the
water extracts, showed strong inhibition against
F. proliferatium and F. solani (an MIC of 0.04 mg/mL). The
ethyl acetate extract of C. molle demonstrated a strong
synergistic effect in combination with an ethyl acetate
extract of Nicotiana glauca against Fusarium proliferatum (an
MIC of 0.001 mg/mL). Strong synergistic effects of the
water extract of C. molle with a water extract of Withania
somnifera against Fusarium proliferatum (an MIC of
0.002 mg/mL). Synergistic effects of acetone extracts of C.
molle with acetone extracts of Quercus acutissima (an MIC of
0.001 mg/mL) against F. proliferatum.
[19]
Combretum molle
Methanol extract of the leaves + kanamycin
and streptomycin
Antibiotic modulation assay using a microdilution
method:
At subinhibitory concentrations (MIC/2 and MIC/4) the
leaf–methanol extract of C. molle resulted in a two- to
sixty-four-fold increase of the antibacterial effects of
kanamycin and streptomycin against Gram-negative
bacteria (e.g., E. coli, Enterobacter aerogenes,
Pseudomonas aeruginosa, Klebsiella pneumoniae, and
Providencia stuartii), including multidrug-resistant clinical
strains. No FIC index values were calculated.
[205]
Abbreviations: FICI—fractional inhibitory concentration index that indicates the quality of the interaction (synergistic, additive, intermediate, or antagonistic); and MIC—minimum inhibitory concentration.
In a comprehensive study by Fankam et al. [205], extracts of Combretum molle, Allanblackia gabonensis, and Gladiolus quartinianus were screened for their interaction effects with
conventional antibiotics on the growth of Gram-negative bacteria, including drug-resistant
phenotypes of E. coli, Enterobacter aerogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa,
and Providencia stuartii. Antibiotic-modulating effects, ranging from 67–100% for methanol
leaf extracts of C. molle in combinations with chloramphenicol, kanamycin, streptomycine,
and tetracycline, were observed against multi-resistant bacteria, and a 64-fold reduction of
the MIC of streptomycin alone was observed in combination with streptomycin against a
multi-drug-resistant strain of E. coli.
The synergistic antimicrobial effects of leaf extracts of Combretum hereroense in combination with leaf extracts of the Citrus lemon and Apodytes dimidiata (Metteniusaceae) species
were investigated against Mycobacterium smegmatis using a microdilution method [31]. The
MICs of the plant combinations ranged from 0.04 mg/mL to 1.25 mg/mL, when compared
to the MICs of 0.1–3 mg/mL for the extracts when tested alone. The combinations that
provided the lowest MIC of 40 µg/mL, i.e., those of an acetone extract of Apodytes diminata
and a hexane extract of Combretum hereroense as well as a combination of dicloromethane
and methanol extracts of the aforementioned species, indicated that the herbal combination
was better than the single-plant-species extracts at inhibiting the growth of M. smegmatis.
Antibiotics 2023, 12, 264
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In a recent study by Seepe et al. [19], a large number of plant species, including Combretum erythrophyllum and C. molle, were screened for their individual and combination
effects against plant-pathogenic Fusarium species. When screened individually, extracts
of Combretum erythrophyllum, Harpephyllum caffrum, and Quercus acutissima were the most
active, with MIC values smaller than 0.1 mg/mL. C. erythrophyllum showed synergistic
or additive effects against all tested Fusarium strains in combinations with Solanum mauritianum, Harpephyllum caffrum, Quercus acutissima, Nicotiana glauca, Withania somnifera, and
Schotia brachypetala. Combined acetone extracts of Harpephyllum caffrum and C. erythrophyllum showed strong, synergistic antifungal activity against F. graminearum, F. proliferatum,
and F. verticillioides (MIC values of 0.02 mg/mL, 0.002 mg/mL and 0.001 mg/mL, respectively). In addition, a combination of the ethyl acetate extracts of the leaves of C. molle and
Nicotiana glauca showed strong synergistic effects against Fusarium proliferatum. Antagonistic effects were detected for some plant extract combinations, such as the ethyl acetate
and acetone extracts of C. molle and C. erythrophyllum against F. proliferatum. The plants
were selected based on their previously reported activity against animal and/or human
fungal pathogens. In summary, this study indicates that combinations of plant extracts are
good alternatives to conventional, synthetic fungicides and supports the established use of
extract combinations in African traditional medicine.
6.2. Nature and Significance of Interactions
Antimicrobial resistance and the adverse effects of antibiotics can be reduced in two
different ways, among other things: by combining antimicrobial plants with each other
or by combining antimicrobial plant extracts, fractions, or compounds with antimicrobial
drugs [31]. Given that the development of new drug therapies for the treatment of infectious
diseases is time-consuming and expensive, it is worth the effort to try different types of
combination therapies [206,207]. Numerous studies have shown that, in combination with
antibiotics, plant extracts and plant-derived compounds increase the activity of antibiotics
and, when allowing for the use of smaller doses of the antibiotics, reduce the side effects
caused by antibiotics. Indeed, these positive interactions are considered a potential strategy
in the fight against bacterial antibiotic resistance, as phytochemicals often act through
different mechanisms than conventional antibiotics and could therefore be useful in the
treatment of infections caused by resistant bacteria. According to current knowledge,
plant-derived compounds modulate and inhibit bacterial resistance mechanisms (e.g.,
the overexpression of efflux pumps, drug inactivating and target-modifying enzymes,
and the transformation of permeation barriers) and thus exhibit synergistic effects with
conventional antibiotics [6,208].
6.3. Putting Synergies into Practice
In African traditional medicine, the interactions of the numerous compounds in
ointments and other herbal preparations made from medicinal plants are utilized when
applied topically for the treatment of wound infections and inflammations on the skin.
Not only are essential oils often used in different combinations, but plant extracts are
also used in combination with each other; for example, in the treatment of skin diseases,
in order to improve the effect [209]. The antifungal potential of the crude extracts of
selected Combretum and Terminalia species and a mixture of asiatic acid and arjunolic
acid isolated from Combretum nelsonii (syn. C. kraussii) was confirmed in a study which
examined the in vivo antifungal effects of plant extracts and compound combinations on
cutaneous wound healing in immunosuppressed rats [83]. Combretum imberbe, Combretum
nelsonii, and Combretum albopunctatum, used in the study by Masoko et al. [83], contain
large concentrations of tannins and other polyphenolic compounds that have a broad
spectrum of antimicrobial activity against skin-related pathogens, supporting the use
of these medicinal plants for dermatological diseases. Moreover, tannin-rich extracts of
Combretum and Pteleopsis could contain tannins with beneficial effects on the bacterial flora
in the gut. Most ellagitannins metabolize to urolithins in the gut, and these metabolites have
Antibiotics 2023, 12, 264
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been considered to have a beneficial effect on health-promoting intestinal bacteria while
reducing the growth of harmful Clostridia [210]. Ahmad et al. [211] suggested that the
methanol leaf extract of Combretum hypopilinum could affect the adrenergic systems in the
antidiarrheal activity. The stem bark n-butanol fraction of Pteleopsis suberosa had anti-ulcer
effects when it was tested with ethanol-induced gastric ulcers in rats and carrageenaninduced paw edema in mice [25].
7. Conclusions
Although many Combretum and Pteleopsis species are utilized in African traditional
medicine, the research and knowledge of the mechanisms underlying the antimicrobial
effects of these plants and their compounds, as well as their synergistic effects with each
other and with antibiotics, is still ongoing and incomplete. A new generation of standardized and effective antimicrobial preparations cannot be developed without comprehensive
information on the antibacterial and antifungal potential of the extracts and the compounds
they contain. In addition, the in vivo testing of activity, toxicity, and bioavailability determines the true role of extracts and compounds from Combretum and Pteleopsis spp. in the
treatment of human infectious diseases.
Although not always used as a selection criterion for antimicrobial screenings, ethnopharmacological knowledge has played a significant role in finding extacts and compounds
with good antimicrobial potential from Combretum and Pteleopsis species. Significantly, the
potent antimicrobial activities of preparations mimicking traditional remedies, such as
macerations and decoctions, have in many cases confirmed the claimed uses in traditional
medicine for the treatment of infections. Altogether, it has been confirmed that a number
of extracts and compounds from the African species of Combretum and Pteleopsis have
promising antimicrobial potential. The most significant antimicrobial activities among the
pure compounds were shown by imberbic acid (with an MIC of 1.56 µg/mL against Mycobacterium fortuitum), arjunglucoside I (with an MIC of 1.9 µg/mL against drug-resistant
Helicobacter pylorii), and pinocembrin (with an MIC of 6.25 µg/mL against C. albicans).
Screenings on the interactions of extracts of Combretum species with conventional
antibiotics or with other plant species are sparse. Furthermore, there are no reported studies
on the combination effects of Pteleopsis species with other plant species or with conventional
antibiotics. However, some studies indicate that extracts of certain species of Combretum
show strong synergistic effects with conventional antibiotics. Of special notice are the
promising potentiating effects of the extracts of Combretum molle on streptomycin against
antibiotic-drug-resistant E. coli. Compounds or standardized extracts of C. molle might have
future uses for drug repurposing against drug-resistant bacteria. So far, no pure compounds
from African Combretum spp. have been evaluated for their combination effects with
antibiotics. However, a mixture of asiatic acid and arjulonic acid, isolated from C. nelsonii
(syn. C. kraussii), was very active against Candida species and Cryptococcus neoformans, with
MIC values between 0.2 and 1.6 µg/mL.
In combination with other plants, as they are used in traditional medicine or for
crop-plant protection, Combretum species show significant synergistic effects, against both
human-pathogenic bacteria and some plant-pathogenic fungi. This justifies the customary
use of Combretum species in combinations with other plants for the treatment of infections
and for crop plant protection in African traditional medicine and agriculture. Moreover,
using extract combinations to combat resistant bacteria and fungi could overcome the
problem of the development of antibiotic resistance due to the multiple components in the
plant extracts.
It is interesting to note that there are no reports on the scientific evaluation of the
antimycobacterial effects of Combretum erythrophyllum and C. micranthum, though both
species are used in traditional medicine for the treatment of tuberculosis. Thus, in-depth
studies on the extracts of these plant species and their bioactive compounds should be
conducted to ascertain their reported use in the treatment of coughs and tuberculosis in
Guinean and African traditional medicine.
Antibiotics 2023, 12, 264
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Author Contributions: H.S., P.F., E.Y.A.S. and E.E.M. designed the study; H.S., E.E.M., E.Y.A.S. and
P.F. wrote the preliminary draft of the manuscript; E.E.M. and P.F. revised the manuscript, edited it,
and cross-checked the literature; P.F secured the funding and supervised the entire study. All authors
have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Swedish Cultural Foundation in Finland, grant number
159102, and the Ekhaga Foundation (Stockhom, Sweden), grant number 2017-07. Open access funding
was provided by Helsinki University Library (HuLib), Finland.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Financial support by the Swedish Cultural Foundation in Finland and the
Ekhaga Foundation (Stockholm, Sweden) is gratefully acknowledged. We thank the Division of
Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Finland for providing
facilities to perform the work. Riitta Julkunen-Tiitto, Professor Emerita, Faculty of Science and
Forestry, Department of Environmental and Biological Sciences, University of Eastern Finland,
Joensuu, is greatly acknowledged for her valuable comments on the manuscript. We thank the
Helsinki University Library (HuLib), Finland for the open access funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Abadi, A.T.B.; Rizvanov, A.A.; Haertlé, T.; Blatt, N.L. World Health Organization Report: Current Crisis of Antibiotic Resistance.
BioNanoScience 2019, 9, 778–788. [CrossRef]
Seung, K.J.; Keshavjee, S.; Rich, M.L. Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Cold Spring
Harb. Perspect. Med. 2015, 5, a017863. [CrossRef] [PubMed]
WHO. World Health Organization, 2019: 2019 Antibacterial Agents in Clinical Development: An Analysis of the Antibacterial Clinical
Development Pipeline; WHO: Geneva, Switzerland, 2019.
Othman, L.; Sleiman, A.; Abdel-Massih, R.M. Antimicrobial activity of polyphenols and alkaloids in Middle Eastern plants. Front.
Microbiol. 2019, 10, 1–28. [CrossRef] [PubMed]
Rex, J.H.; Walsh, T.J.; Sobel, J.D. Practice guidelines for the treatment of candidiasis. Clin. Infect. Dis. 2000, 30, 662–678. [CrossRef]
Abreu, A.C.; McBain, A.J.; Simões, M. Plants as sources of new antimicrobials and resistance-modifying agents. Nat. Prod. Rep.
2012, 29, 1007–1021. [CrossRef]
Abreu, A.C.; Coqueiro, A.; Sultan, A.R.; Lemmens, N.; Kim, H.K.; Verpoorte, R.; Van Wamel, W.J.B.; Simões, M.; Choi, Y.H.
Looking to nature for a new concept in antimicrobial treatments: Isoflavonoids from Cytisus striatus as antibiotic adjuvants
against MRSA. Sci Rep. 2017, 7, 3777. [CrossRef]
Mahomoodally, M.F. Traditional medicines in Africa: An appraisal of ten potent African medicinal plants. Evid. Based Complementary Altern. Med. 2013, 2013, 617459. [CrossRef]
Tsobou, R.; Mapongmetsem, P.M.; Van Damme, P. Medicinal plants used for treating reproductive health care problems in
Cameroon, Central Africa. Econ Bot. 2016, 70, 145–159. [CrossRef]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629–661. [CrossRef]
Taofiq, O.; González-Paramás, A.M.; Barreiro, M.F.; Ferreira, I.C.F.R. Hydroxycinnamic acids and their derivatives: Cosmeceutical
significance, challenges and future perspectives, a review. Molecules 2017, 22, 281. [CrossRef]
Prasad, M.A.; Zolnik, C.P.; Molina, J. Leveraging phytochemicals: The plant phylogeny predicts sources of novel antibacterial
compounds. Future Sci. 2019, 5, 124. [CrossRef] [PubMed]
Eloff, J.N.; Katerere, D.R.; McGaw, L.J. The biological activity and chemistry of the southern African Combretaceae. J. Ethnopharmacol. 2008, 119, 686–699. [CrossRef] [PubMed]
McGaw, L.J.; Rabe, T.; Sparg, S.G.; Jäger, A.K.; Eloff, J.N.; Van Staden, J. An investigation of the biological activity of Combretum
species. J. Ethnopharmacol. 2001, 75, 45–50. [CrossRef] [PubMed]
Dawe, A.; Pierre, S.; Tsala, D.E.; Habtemariam, S. Phytochemical constituents of Combretum Loefl. (Combretaceae). Pharm. Crops.
2013, 4, 38–59. [CrossRef]
Jordaan, M.; Van Wyk, A.E.; Maurin, O. A conspectus of Combretum (Combretaceae) in southern Africa, with taxonomic and
nomenclatural notes on species and sections. Bothalia 2011, 41, 135–160. [CrossRef]
Fyhrquist, P.; Mwasumbi, L.; Hæggström, C.-A.; Vuorela, H.; Hiltunen, R.; Vuorela, P. Antifungal activity of selected species of
Terminalia, Pteleopsis and Combretum (Combretaceae) collected in Tanzania. Pharm. Biol. 2004, 42, 308–317. [CrossRef]
Antibiotics 2023, 12, 264
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
45 of 52
Tilney, P.M. A contribution to the leaf and young stem anatomy of the Combretaceae. Bot. J. Linn. Soc. 2002, 138, 163–196.
[CrossRef]
Seepe, H.A.; Amoo, S.O.; Nxumalo, W.; Adeleke, R.A. Sustainable use of thirteen South African medicinal plants for the
management of crop diseases caused by Fusarium species—An in vitro study. S. Afr. J. Bot. 2020, 130, 456–464. [CrossRef]
Rahate, S.; Hemke, A.; Umekar, M. Review on Combretaceae family. Int. J. Pharm. Sci. Rev. Res. 2019, 58, 22–29.
Roy, S.; Gorai, D.; Acharya, R.; Roy, R. Combretum (combretaceae): Biological activity and phytochemistry. Indo Am. J. Pharm Res.
2014, 4, 5266–5299.
Cock, I.E.; Van Vuuren, S.F. The traditional use of southern African medicinal plants for the treatment of bacterial respiratory
diseases: A review of the ethnobotany and scientific evaluations. J. Ethnopharmacol. 2020, 263, 113204. [CrossRef] [PubMed]
Fyhrquist, P.; Salih, E.Y.A.; Helenius, S.; Laakso, I.; Julkunen-Tiitto, R. HPLC-DAD and UHPLC/QTOF-MS analysis of polyphenols
in extracts of the African Species Combretum padoides, C. zeyheri and C. psidioides related to their antimycobacterial activity.
Antibiotics 2020, 9, 459. [CrossRef] [PubMed]
De Pasquale, R.; Germano, M.P.; Keita, A.; Sanogo, R.; Iauk, L. Antiulcer activity of Pteleopsis suberosa. J. Ethnopharmacol. 1995, 47,
55–58. [CrossRef] [PubMed]
Germanò, M.P.; D’Angelo, V.; Biasini, T.; Miano, T.C.; Braca, A.; De Leo, M.; De Pasquale, R.; Sanogo, R. Anti-Ulcer, antiinflammatory and antioxidant activities of the n-butanol fraction from Pteleopsis suberosa stem bark. J. Ethnopharmacol. 2008, 115,
271–275. [CrossRef]
Angeh, J.E.; Huang, X.; Sattler, I.; Swan, G.E.; Dahse, H.; Härtl, A.; Eloff, J.N. Antimicrobial and anti-inflammatory activity of four
known and one new triterpenoid from Combretum imberbe (Combretaceae). J. Ethnopharmacol. 2007, 110, 56–60. [CrossRef]
Welch, C.; Zheng, J.; Bassène, E.; Raskin, I.; Simon, J.E.; Wu, Q. Bioactive polyphenols in kinkéliba tea (Combretum micranthum)
and their glucose-lowering activities. J. Food Drug Anal. 2018, 26, 487–496. [CrossRef]
de Morais Lima, G.R.; de Sales, I.R.; Caldas Filho, M.R.; de Jesus, N.Z.; de Sousa Falcão, H.; Barbosa-Filho, J.M.; Cabral, A.G.;
Souto, A.L.; Tavares, J.F.; Batista, L.M. Bioactivities of the genus Combretum (Combretaceae): A Review. Molecules 2012, 17,
9142–9206. [CrossRef]
Cock, I.E.; Van Vuuren, S.F. A comparison of the antimicrobial activity and toxicity of six Combretum and two Terminalia species
from Southern Africa. Pharmacogn. Mag. 2015, 11, 149740. [CrossRef]
Chukwujekwu, J.C.; Van Staden, J. In vitro antibacterial activity of Combretum edwardsii, Combretum krausii, and Maytenus nemorosa
and their synergistic effects in combination with antibiotics. Front. Pharmacol. 2016, 7, 208. [CrossRef]
Komape, N.P.M.; Bagla, V.P.; Kabongo-Kayoka, P.; Masoko, P. Anti-mycobacterial potential and synergistic effects of combined
crude extracts of selected medicinal plants used by Bapedi traditional healers to treat tuberculosis related symptoms in Limpopo
Province, South Africa. BMC Complement Altern Med. 2017, 17, 128. [CrossRef]
Gurib-Fakim, A. Medicinal plants: Traditions of yesterday and drugs of tomorrow. Mol. Aspects Med. 2006, 27, 1–93. [CrossRef]
[PubMed]
Muthu, C.; Ayyanar, M.; Raja, N.; Ignacimuthu, S. Medicinal plants used by traditional healers in Kancheepuram District of Tamil
Nadu, India. J. Ethnobiol. Ethnomed. 2006, 2, 43. [CrossRef]
Uzor, P.F.; Ebrahim, W.; Osadebe, P.O.; Nwodo, J.N.; Okoye, F.B.; Müller, W.E.G.; Lin, W.; Liu, Z.; Proksch, P. Metabolites
from Combretum dolichopetalum and its associated endophytic fungus Nigrospora oryzae—Evidence for a metabolic partnership.
Fitoterapia 2015, 105, 147–150. [CrossRef]
Watt, J.M.; Breyer-Brandwijk, M.G. The Medicinal and Poisonous Plants of Southern and Eastern Africa Being an Account of Their
Medicinal and Other Uses, Chemical Composition, Pharmacological Effects and Toxicology in Man and Animal, 2nd ed.; E & S. Livingstone
Ltd.: Edinburgh, Scotland, 1962.
Fyhrquist, P.; Mwasumbi, L.; Hæggström, C.-A.; Vuorela, H.; Hiltunen, R.; Vuorela, P. Ethnobotanical and antimicrobial
investigation of some species of Terminalia and Combretum (Combretaceae) growing in Tanzania. J. Ethnopharmacol. 2002, 79,
169–177. [CrossRef]
Rasethe, M.T.; Semenya, S.S.; Maroyi, A. Medicinal plants traded in informal herbal medicine markets of the Limpopo province,
South Africa. Evid. Based Compl. Altern. Med. 2019, 2019, 2609532. [CrossRef]
Xavier, C.; Molina, J. Phylogeny of medicinal plants depicts cultural convergence among immigrant groups in New York City.
J. Herb. Med. 2016, 6, 1–11. [CrossRef]
Schmelzer, G.H.; Gurib-Fakim, A. (Eds.) Plant Resources of Tropical Africa 11(1). Medicinal Plants 1; PROTA Foundation: Wageningen,
The Netherlands; Backhuys Publishers: Leiden, The Netherlands; CTA: Waningenen, The Netherlands, 2008; 791p.
Anato, M.; Ketema, T. Anti-plasmodial activities of Combretum molle (Combretaceae) [Zwoo] seed extract in Swiss albino mice.
BMC Res. Notes 2018, 11, 312. [CrossRef]
Rademan, S.; Lall, N. Combretum molle. In Underexplored Medicinal Plants from Sub-Saharan Africa-Plants with Therapeutic Potential
for Human Health; Academic Press, Elsevier: Amsterdam, The Netherlands, 2019.
Grønhaug, T.E.; Glæserud, S.; Skogsrud, M.; Ballo, N.; Bah, S.; Diallo, D.; Paulsen, B.S. Ethnopharmacological survey of six
medicinal plants from Mali, West-Africa. J. Ethnobiol. Ethnomed. 2008, 2008, 4. [CrossRef] [PubMed]
Antibiotics 2023, 12, 264
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
46 of 52
Asres, K.; Mazumder, A.; Bucar, F. Antibacterial and antifungal activities of extracts of Combretum molle. Ethiop. Med. J. 2006, 44,
269–277. [PubMed]
Augustino, S.; Gillah, P.R. Medicinal plants in urban districts of Tanzania: Plants, gender roles and sustainable use. Int. For. Rev.
2005, 7, 44–58. [CrossRef]
Welch, C.R. Chemistry and Pharmacology of Kinkéliba (Combretum micranthum), a West African Medicinal Plant. Ph.D. Thesis,
Rutgers University, Medicinal Chemistry, Piscataway, NJ, USA, 2010; 283p.
Baba-Moussa, F.; Akpagana, K.; Bouchet, P. Antifungal activities of seven West African Combretaceae used in traditional medicine.
J. Ethnopharmacol. 1999, 66, 335–338. [CrossRef] [PubMed]
Benoit, F.; Valentin, A.; Pelissier, F.; Diafouka, F.; Marion, C.; Kone-Bamba, D.; Kone, M.; Mallie, M.; Yapo, A.; Bastide, J.-M.
In vitro Antimalarial activity of vegetal extracts used in West-African traditional medicine. Am. J. Trop. Med. Hyg. 1996, 54, 67–71.
[CrossRef]
Bonkian, L.N.; Yerbanga, R.S.; Traoré/Coulibaly, M.; Lefèvre, T.; Sangaré, I.; Ouédraogo, T.; Traore, O.; Ouédraogo, J.B.;
Guiguemde, T.R.; Dabiré, K.R. Plants against Malaria and Mosquitoes in Sahel region of Burkina Faso: An Ethno-botanical survey.
Int. J. Herb. Med. 2017, 5, 82–87.
Keïta, J.N.; Diarra, N.; Kone, D.; Tounkara, H.; Dembele, F.; Coulibaly, M.; Traore, N. Medicinal plants used against malaria by
traditional therapists in malaria endemic areas of the Ségou region, Mali. J. Med. Plants Res. 2020, 14, 480–487.
Madikizela, B.; Ndhlala, A.R.; Finnie, J.F.; Van Staden, J. Antimycobacterial, anti-inflammatory and genotoxicity evaluation
of plants used for the treatment of tuberculosis and related symptoms in South Africa. J. Ethnopharmacol. 2014, 153, 386–391.
[CrossRef]
Magwenzi, R.; Nyakunu, C.; Mukanganyama, S. The effect of selected Combretum species from Zimbabwe on the growth and
drug efflux systems of Mycobacterium aurum and Mycobacterium smegmatis. J. Microbial. Biochem. Technol. 2014, S3, 3. [CrossRef]
Ribeiro, A.; Romeiras, M.M.; Tavares, J.; Faria, M.T. Ethnobotanical survey in Canhane village, district of Massingir, Mozambique:
Medicinal plants and traditional knowledge. J. Ethnobiol. Ethnomed. 2010, 6, 33. [CrossRef]
Chinsembu, K.C.; Hedimbi, M. An ethnobotanical survey of plants used to manage HIV/AIDS opportunistic infections in Katima
Mulilo, Caprivi region, Namibia. J. Ethnobiol. Ethnomed. 2010, 6, 1. [CrossRef]
Chinsembu, K.C.; Hijarunguru, A.; Mbangu, A. Ethnomedicinal plants used by traditional healers in the management of
HIV/AIDS opportunistic diseases in Rundu, Kavango East Region, Namibia. S. Afr. J. Bot. 2015, 100, 33–42. [CrossRef]
Chinsembu, K.C. Ethnobotanical study of medicinal flora utilised by traditional healers in the management of sexually transmitted
infections in Sesheke District, Western Province, Zambia. Rev. Bras. Farmacogn. 2016, 26, 30. [CrossRef]
Cheikhyoussef, A.; Shapi, M.; Matengu, K.; Ashekele, H.M. Ethnobotanical study of indigenous knowledge on medicinal plant
use by traditional healers in Oshikoto region, Namibia. J. Ethnobiol. Ethnomed. 2011, 7, 1–11. [CrossRef] [PubMed]
Dan, V.; Mchombu, K.; Mosimane, A. Indigenous medicinal knowledge of the San people: The case of Farm Six, Northern
Namibia. Inf. Dev. 2010, 26, 129–140. [CrossRef]
Dzomba, P.; Chayamiti, T.; Nyoni, S.; Munosiyei, P.; Gwizangwe, I. Ferriprotoporphyrin IX-Combretum imberbe crude extracts
interactions: Implication for malaria treatment. Afr. J. Pharm. Pharmacol. 2012, 6, 2205–2210. [CrossRef]
Drummond, R.B.; Coates-Palgrave, K. Common Trees of the Highweld; Longman Rhodesia: Rhodesia, South Africa, 1973.
Martini, N.D.; Katerere, D.R.; Eloff, J.N. Seven flavonoids with antibacterial activity isolated from Combretum erythrophyllum.
S. Afr. J. Bot. 2004, 70, 310–312. [CrossRef]
Mawoza, T.; Ndove, T. Combretum erythrophyllum (Burch.) Sond. (Combretaceae): A review of its ethnomedicinal uses, phytochemistry and pharmacology. Glob. J. Biol. Agric. Health Sci. 2015, 4, 105–109.
Thulin, M. Flora of Somalia; The University of Chicago Press: Chicago, IL, USA, 1993; Volume 1, 501p.
Hamad, K.M.; Sabry, M.M.; Elgayed, S.H.; El Shabrawy, A.-R.; El-Fishawy, A.M. Pharmacognostical Study of Combretum
aculeatum Vent. Growing in Sudan. In Bulletin of Faculty of Pharmacy; Cairo University: Cairo, Egypt, 2019; Volume 57, No. 2.
Salih, E.Y.A. Ethnobotany, Phytochemistry and Antimicrobial Activity of Combretum, Terminalia and Anogeissus Species (Combretaceae)
Growing Naturally in Sudan. Ph.D. Thesis, University of Helsinki, Helsinki, Finland, 2019. Tropical Forestry Reports 50. 193p.
Diop, E.H.A.; Queiroz, E.F.; Marcourt, L. Antimycobacterial activity in a single-cell infection assay of ellagitannins from Combretum
aculeatum and their bioavailable metabolites. J. Ethnopharmacol. 2019, 238, 111832. [CrossRef] [PubMed]
Kerharo, J.; Adam, J.G. La Pharmacopée Sénégalaise Traditionelle- Plantes Médicinales et Toxiques; Frères, V., Ed.; Paris (France) Vigot:
Paris, France, 1974.
Wickens, G.E. Flora of Tropical East Africa. Combretaceae; East African Community, Royal Botanic Gardens: Kew, London, UK, 1973;
99p.
Dawé, A.; Mbiantcha, M.; Yakai, F.; Jabeen, A.; Ali, M.S.; Lateef, M.; Ngadjui, B.T. Flavonoids and triterpenes from Combretum
fragrans with anti-inflammatory, antioxidant and antidiabetic potential. Z. Naturforsch. 2018, 73, 211–219. [CrossRef]
Kokwaro, J.O. Medicinal Plants of East Africa; East African Literature Bureau: Nairobi, Kenya, 1976.
Chhabra, S.C.; Mahunnah, R.L.A.; Mshiu, E.N. Plants used in traditional medicine in Eastern Tanzania. II. Angiosperms
(Capparidaceae to Ebenaceae). J. Ethnopharmacol. 1989, 25, 339–359. [CrossRef]
Antibiotics 2023, 12, 264
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
47 of 52
Hedberg, I.; Hedberg, O.; Madati, P.J.; Mshigeni, K.E.; Mshiu, E.N.; Samuelsson, G. Inventory of plants used in traditional
medicine in Tanzania. I. Plants of the families Acanthaceae-Cucurbitaceae. J. Ethnopharmacol. 1982, 6, 29–60. [CrossRef]
Rogers, C.B.; Coombes, P.H. Acidic triterpene glycosides in trichome secretions differentiate subspecies of Combretum collinum in
South Africa. Biochem. Syst. Ecol. 1999, 27, 321–323. [CrossRef]
Zenebe, G.; Zerihun, M.; Solomon, Z. An ethnobotanical study of medicinal plants in Asgede Tsimbila district, Northwestern
Tigray, Northern Ethiopia. Ethnobot. Res. Appl. 2012, 10, 305–320. [CrossRef]
Elegami, A.A.; El-Nima, E.I.; El Tohami, M.S.; Muddathir, A.K. Antimicrobial activity of some species of the family Combretaceae.
Phytother Res. 2002, 16, 555–561. [CrossRef] [PubMed]
Eldeen, I.M.S.; Van Staden, J. In vitro pharmacological investigation of extracts from some trees used in Sudanese traditional
medicine. S. Afr. J. Bot. 2007, 73, 435–440. [CrossRef]
Salih, E.Y.A.; Julkunen-Tiitto, R.; Luukkanen, O.; Fahmi, M.K.M.; Fyhrquist, P. Hydrolyzable tannins (ellagitannins), flavonoids,
pentacyclic triterpenes and their glycosides in antimycobacterial extracts of the ethnopharmacologically selected Sudanese
medicinal plant Combretum hartmannianum Schweinf. 2021. Biomed. Pharmacother. 2021, 144, 112264. [CrossRef] [PubMed]
El Ghazali, G.E.B.; El Tohami, M.S.; El Egami, A.A. Medicinal Plants of the Sudan. Part III. Medicinal Plants of the White Nile Province;
National Center for Research: Khartoum, Sudan, 1994.
Muddathir, A.M.; Mitsunaga, T. Evaluation of anti-acne activity of selected Sudanese medicinal plants. J. Wood Sci. 2013, 59,
73–79. [CrossRef]
Samuelsson, G.; Farah, M.H.; Claeson, P.; Hagos, M.; Thulin, M.; Hedberg, O.; Alin, M.H. Inventory of plants used in traditional
medicine in Somalia. I. Plants of the families Acanthaceae-Chenopodiaceae. J. Ethnopharmacol. 1991, 35, 25–63. [CrossRef]
Neuwinger, H.D. African Traditional Medicine: A Dictionary of Plant Use and Applications. With Supplement: Search System for Diseases;
Medpharm: Stuttgart, Germany, 2000; 599p. Available online: https://www.cabdirect.org/cabdirect/abstract/20026790056
(accessed on 14 December 2022).
Regassa, F.; Araya, M. In vitro antimicrobial activity of Combretum molle (Combretaceae) against Staphylococcus aureus and
Streptococcus agalactiae isolated from crossbred dairy cows with clinical mastitis. Trop. Anim. Health Prod. 2012, 44, 1169–1173.
[CrossRef]
Masoko, P.; Mdee, L.K.; Mampuru, L.J.; Eloff, J.N. Biological activity of two related triterpenes isolated from Combretum nelsonii
(Combretaceae) leaves. Nat. Prod. Res. 2008, 22, 1074–1084. [CrossRef]
Masoko, P.; Picard, J.; Howard, R.L.; Mampuru, L.J.; Eloff, J.N. In vivo antifungal effect of Combretum and Terminalia species
extracts on cutaneous wound healing in immunosuppressed rats. Pharm. Biol. 2010, 48, 621–632. [CrossRef]
Abreu, P.M.; Martins, E.S.; Kayser, O.; Bindseil, K.-U.; Siems, K.; Seemann, A.; Frevert, J. Antimicrobial, antitumor and
antileishmania screening of Medicinal Plants from Guinea-Bissau. Phytomedicine 1999, 6, 187–195. [CrossRef]
Inngjerdingen, K.; Nergård, C.S.; Diallo, D.; Mounkoro, P.P.; Paulsen, B.S. An ethnopharmacological survey of plants used for
wound healing in Dogonland, Mali, West Africa. J. Ethnopharmacol. 2004, 92, 233–244. [CrossRef] [PubMed]
Van-Wyk, B.; Van-Wyk, P. Field Guide to Trees of Southern Africa; Struik Publishers: Cape Town, South Africa, 1997; 525p.
Burkill, H.M. The Useful Plants of West Tropical Africa. In Combretum nigricans Lepr. [family COMBRETACEAE]; Royal Botanic
Gardens: Kew, London, UK, 1985; Volume 1, p. 981.
Chinedu, E.; Akah, P.A.; Jacob, D.L.; Onah, I.A.; Ukegbu, C.Y.; Chukwuemeka, C.K. Antimalarial activities of butanol and
ethylacetate fractions of Combretum nigricans leaf. Asian Pac. J. Trop. Biomed. 2019, 9, 176–180. [CrossRef]
Ahmed, A.S.; McGaw, L.J.; Elgorashi, E.E.; Naidoo, V.; Eloff, J.N. Polarity of extracts and fractions of four Combretum (Combretaceae) species used to treat infections and gastrointestinal disorders in southern African traditional medicine has a major effect
on different relevant in vitro activities. J. Ethnopharmacol. 2014, 154, 339–350. [CrossRef] [PubMed]
Ngounou, N.F.; Atta-Ur-Rahman; Choudhary, M.I.; Malik, S.; Zareen, S.; Ali, R.; Lontsi, D. Two saponins from Pteleopsis
hylodendron. Phytochemistry 1999, 52, 917–921. [CrossRef]
Nana, H.M.; Ngane, R.A.N.; Kuiate, J.R.; Koanga Mogtomo, L.M.; Tamokoua, J.D.; Ndifor, F.; Mouokeu, R.S.; Ebelle Etame,
R.M.; Biyiti, L.; Amvam Zollo, P.H. Acute and sub-acute toxicity of the methanolic extract of Pteleopsis hylodendron stem bark.
J. Ethnopharmacol. 2011, 137, 70–76. [CrossRef] [PubMed]
Manuel, L.; Bechel, A.; Noormahomed, E.V.; Hlashwayo, D.F.; Madureira, M.d.C. Ethnobotanical study of plants used by the
traditional healers to treat malaria in Mogovolas district, northern Mozambique. Heliyon 2020, 6, e05746. [CrossRef] [PubMed]
Dharani, N. Field Guide to Common Trees & Shrubs of East Africa, 3rd ed.; Alves, C., Ed.; Struik Nature: Western Cape, South Africa, 2019.
ventory of
us
Magwede, K.; van Wyk, B.; van Wyk, A.E. An inventory
of Vhavenḓa
Vhaven a useful
plants. S. Afr. J. Bot. 2019, 122, 57–89. [CrossRef]
De Leo, M.; De Tommasi, N.; Sanogo, R.; D’Angelo, V.; Germanó, M.P.; Bisignano, G.; Braca, A. Triterpenoid saponins from
Pteleopsis suberosa stem bark. Phytochemistry. 2006, 67, 2623–2629. [CrossRef]
Raliat, A.A.; Saheed, S.; Abdulhakeem, S.O. Pteleopsis suberosa Engl. and Diels (Combretaceae) aqueous stem bark extract
extenuates oxidative damage in streptozotocin-induced diabetic Wistar rats. Pharmacogn. J. 2019, 11, 183–190. [CrossRef]
Bhavani, P.K.; Aik, W.T.; Basil, D.R. Pharmacology of traditional herbal medicines and their active principles used in the treatment
of peptic ulcer, diarrhoea and inflammatory bowel disease. New Adv. Basic Clin. Gastroenterol. 2012, 14, 297–310.
Akintunde, J.K.; Babaita, A.K. Effect of PUFAs from Pteleopsis suberosa stem bark on androgenic enzymes, cellular ATP and keratic
acid phosphatase in mercury chloride—Exposed rat. Middle East Fertil. Soc. J. 2017, 22, 211–218. [CrossRef]
Antibiotics 2023, 12, 264
48 of 52
99. Van Andel, T.; Myren, B.; Van Onselen, S. Ghana’s herbal market. J. Ethnopharmacol. 2012, 140, 368–378. [CrossRef]
100. Borrelli, F.; Izzo, A.A. The Plant Kingdom as a Source of Anti-ulcer Remedies. Phytother. Res. 2000, 14, 581–591. [CrossRef]
[PubMed]
101. Pedersen, M.E.; Vestergaard, H.T.; Hansen, S.L.; Bah, S.; Diallo, D.; Jäger, A.K. Pharmacological screening of Malian medicinal
plants used against epilepsy and convulsions. J. Ethnopharmacol. 2009, 121, 472–475. [CrossRef] [PubMed]
102. Quiroz, D.; Towns, A.; Legba, S.I.; Swier, J.; Brière, S.; Sosef, M.; Van Andel, T. Quantifying the domestic market in herbal medicine
in Benin, West Africa. J. Ethnopharmacol. 2014, 151, 1100–1108. [CrossRef] [PubMed]
103. Fanou, B.A.; Klotoe, J.R.; Fah, L.; Dougnon, V.; Koudokpon, C.H.; Toko, G.; Loko, F. Ethnobotanical survey on plants used in the
treatment of candidiasis in traditional markets of southern Benin. BMC Complement. Med. Ther. 2020, 20, 1–18. [CrossRef]
104. Tapsoba, H.; Deschamps, J.-P. Use of medicinal plants for the treatment of oral diseases in Burkina Faso. J. Ethnopharmacol. 2006,
104, 68–78. [CrossRef]
105. El Amin, H.E. Trees and Shrubs of the Sudan; Ithaea Press: Exeter, UK, 1990.
106. Von Maydell, H.J. Trees and Shrubs of the Sahel, Their Characteristics and Uses (No. 196); TZ Verlagsgesellschaft, GTZ: Germany, 1986;
ISBN 3880853185.
107. Eloff, J.N. The antibacterial activity of 27 Southern African members of the Combretaceae. S. Afr. J. Sci. 1999, 95, 148–152.
108. Masoko, P.; Picard, J.; Eloff, J.N. The antifungal activity of twenty-four southern African Combretum species (Combretaceae).
S. Afr. J. Bot. 2007, 73, 173–183. [CrossRef]
109. Anokwuru, C.P.; Sandasi, M.; Chen, W.; Van Vuuren, S.; Elisha, I.L.; Combrinck, S.; Viljoen, A.M. Investigating antimicrobial
compounds in South African Combretaceae species using a biochemometric approach. J. Ethnopharmacol. 2021, 269, 113681.
[CrossRef]
110. Lall, N.; Meyer, J.J.M. In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by ethnobotanically selected South African plants. J. Ethnopharmacol. 1999, 66, 347–354. [CrossRef] [PubMed]
111. Asres, K.; Bucar, F.; Edelsbrunner, S.; Kartnig, T.; Höger, G.; Thiel, W. Investigations on Antimycobacterial Activity of Some
Ethiopian Medicinal Plants. Phytother. Res. 2001, 15, 323–326. [CrossRef] [PubMed]
112. Eldeen, I.M.S.; Van Staden, J. Cyclooxygenase inhibition and antimycobacterial effects of extracts from Sudanese medicinal plants.
S. Afr. J. Bot. 2008, 74, 225–229. [CrossRef]
113. Masoko, P.; Nxumalo, K.M. Validation of antimycobacterial plants used by traditional healers in three districts of the Limpopo
Province (South Africa). Evid. Based Complementary Altern. Med. 2013, 2013, 586247. [CrossRef]
114. Martini, N.D.; Eloff, J.N. The preliminary isolation of several antibacterial compounds from Combretum erythrophyllum (Combretaceae). J. Ethnopharmacol. 1998, 62, 255–263. [CrossRef]
115. Saraiva, A.M.; Castro, R.H.A.; Cordeiro, R.P.; Sobrinho, T.J.S.P.; Castro, V.T.N.A.; Amorim, E.L.C.; Xavier, H.S.; Pisciottano, M.N.C.
In vitro evaluation of antioxidant, antimicrobial and toxicity properties of extracts of Schinopsis brasiliensis Engl. (Anacardiaceae).
Afr. J. Pharm. Pharmacol. 2011, 5, 1724–1731. [CrossRef]
116. Maregesi, S.M.; Pieters, L.; Ngassapa, O.D.; Apers, S.; Vingerhoets, R.; Cos, P.; Berghe, D.A.V.; Vlietinck, A.J. Screening of some
Tanzanian medicinal plants from Bunda district for antibacterial, antifungal and antiviral activities. J. Ethnopharmacol. 2008, 119,
58–66. [CrossRef]
117. Batawila, K.; Kokou, K.; Koumaglo, K.; Gbeassor, M.; de Foucault, B.; Bouchet, P.; Akpagana, K. Antifungal activities of five
Combretaceae used in Togolese traditional medicine. Fitoterapia 2005, 76, 264–268. [CrossRef]
118. Vroumsia, T.; Saotoing, P.; Dawé, A.; Djaouda, M.; Ekaney, M.; Mua, B. The sensitivity of Escherichia coli to extracts of Combretum
fragrans, Combretum micranthum and Combretum molle locally used in the treatment of diarrheal diseases in the Far-North Region
of Cameroon. Int. J. Curr. Microbiol. Appl. Sci. 2015, 4, 399–411.
119. Vandeputte, O.M.; Kiendrebeogo, M.; Rajaonson, S.; Diallo, B.; Mol, A.; El Jaziri, M.; Baucher, M. Identification of catechin as one
of the flavonoids from Combretum albiflorum bark extract that reduces the production of quorum-sensing-controlled virulence
factors in Pseudomonas aeruginosa PAO1. Appl. Environ. Microbiol. 2010, 76, 243–253. [CrossRef]
120. McGaw, L.J.; Jager, A.K.; Van Staden, J. Antibacterial, anthelmintic and anti-amoebic activity in South African medicinal plants.
J. Ethnopharmacol. 2000, 72, 247–263. [CrossRef] [PubMed]
121. Netshiluvhi, T.R.; Eloff, J.N. Influence of annual rainfall on antibacterial activity of acetone leaf extracts of selected medicinal
trees. S. Afr. J. Bot. 2016, 102, 197–201. [CrossRef]
122. Mohieldin, E.A.M.; Muddathir, A.M.; Mitsunaga, T. Inhibitory activities of selected Sudanese medicinal plants on Porphyromonas
gingivalis and matrix metalloproteinase-9 and isolation of bioactive compounds from Combretum hartmannianum (Schweinf) bark.
BMC Complement. Altern. Med. 2017, 17, 224. [CrossRef] [PubMed]
123. Eldeen, I.M.S.; Elgorashi, E.E.; Van Staden, J. Antibacterial, anti-inflammatory, anti-cholinesterase and mutagenic effects of
extracts obtained from some trees used in South African traditional medicine. J. Ethnopharmacol. 2005, 102, 457–464. [CrossRef]
124. Udoh, I.P.; Nworu, C.S.; Eleazar, C.I.; Onyemelukwe, F.N.; Esimone, C.O. Antibacterial profile of extracts of Combretum micranthum
G. Don against resistant and sensitive nosocomial isolates. J. Appl. Pharm. Sci. 2012, 2, 142–146. [CrossRef]
125. Muraina, I.A.; Adaudi, A.O.; Mamman, M.; Kazeem, H.M.; Picard, J.; McGaw, L.J.; Eloff, J.N. Antimycoplasmal activity of some
plant species from northern Nigeria compared to the currently used therapeutic agent. Pharm Biol. 2010, 48, 1103–1107. [CrossRef]
Antibiotics 2023, 12, 264
49 of 52
126. Akeem, A.A.; Ejikeme, U.C.; Okarafor, E.U. Antibacterial potentials of the ethanolic extract of the stem bark of Combretum
micranthum G. Don and its fractions. J. Plant Stud. 2012, 1, 75.
127. Kotze, M.; Eloff, J.N. Extraction of antibacterial compounds from Combretum microphyllum (Combretaceae). S. Afr. J. Bot. 2002, 68,
62–67. [CrossRef]
128. Steenkamp, V.; Fernandes, A.C.; Van Rensburg, C.E. Antibacterial activity of Venda medicinal plants. Fitoterapia 2007, 78, 561–564.
[CrossRef]
129. Geyid, A.; Abebe, D.; Debella, A.; Makonnen, Z.; Aberra, F.; Teka, F.; Kebede, T.; Urga, K.; Yersaw, K.; Biza, T.; et al. Screening of
some medicinal plants of Ethiopia for their anti-microbial properties and chemical profiles. J. Ethnopharmacol. 2005, 97, 421–427.
[CrossRef]
130. Mogashoa, M.M.; Eloff, J.N. Different Combretum molle (Combretaceae) leaf extracts contain several different antifungal and
antibacterial compounds. S. Afr. J. Bot. 2019, 126, 322–327. [CrossRef]
131. Sawhney, A.M.; Khan, M.R.; Ndaalio, G.; Nkunya, M.H.H.; Wevers, H. Studies on the rationale of African traditional medicine.
Part III. Preliminary screening of medicinal plants for antifungal activity. Pak. J. Sci. Ind. Res. 1978, 21, 193–196.
132. Masengu, C.; Zimba, F.; Mangoyi, R.; Mukanganyama, S. Inhibitory activity of Combretum zeyheri and its S9 metabolites against
Escherichia coli, Bacillus subtilis and Candida albicans. J. Microb. Biochem. Technol. 2014, 6, 228–235. [CrossRef]
133. Maregesi, S.M.; Ngassapa, O.D.; Pieters, L.; Vlietinck, A.J. Ethnopharmacological survey of the Bunda district, Tanzania: Plants
used to treat infectious diseases. J. Ethnopharmacol. 2007, 113, 457–470. [CrossRef]
134. Mapfunde, S.; Sithole, S.; Mukanganyama, S. In vitro toxicity determination of antifungal constituents from Combretum zeyheri.
BMC Complement Altern. Med. 2016, 16, 162. [CrossRef] [PubMed]
135. Nyambuya, T.; Mautsa, R.; Mukanganyama, S. Alkaloid extracts from Combretum zeyheri inhibit the growth of Mycobacterium
smegmatis. BMC Complement Altern. Med. 2017, 17, 124. [CrossRef] [PubMed]
136. Karou, D.; Dicko, M.H.; Simpore, J.; Traore, A.S. Antioxidant and antibacterial activities of polyphenols from ethnomedicinal
plants of Burkina Faso. Afr. J. Biotechnol. 2005, 4, 823–828.
137. Kola, K.A.; Benjamin, A.E. Comparative antimicrobial activities of the leaves of Combretum micranthum and C. Racemosum. Global
J. Med. Sci. 2002, 1, 13–17. [CrossRef]
138. Banfi, S.; Caruso, E.; Orlandi, V.; Barbieri, P.; Cavallari, S.; Viganò, P.; Clerici, P.; Chiodaroli, L. Antibacterial activity of leaf extracts
from combretum micranthum and guiera senegalensis (Combretaceae). Res. J. Microbiol. 2014, 9, 66–81. [CrossRef]
139. Mokale Kognou, A.L.; Ngono Ngane, R.A.; Kuiate, J.R.; Koanga Mogtomo, M.L.; Tchinda Tiabou, A.; Mouokeu, R.S.; Biyiti, L.;
Amvam Zollo, P.H. Antibacterial and antioxidant properties of the methanolic extract of the stem bark of Pteleopsis hylodendron
(Combretaceae). Chemother. Res. Pract. 2011, 2011, 218750. [CrossRef]
140. Muhammad, S.L. Phytochemical screening and antimicrobial activities of crude methanolic extract of Pteleopsis Habeensis (Aubrev
Ex Keay) stem bark against drug resistant bacteria and fungi. Int. J. Technol. Res. Appl. 2014, 2, 26–30.
141. Bisignano, G.; Germano, M.P.; Nostro, A.; Sanogo, R. Drugs used in Africa as Dyes: II. Antimicrobial activities. Phytother. Res.
1996, 10, 161–163.
142. Germano, M.P.; Sanogo, R.; Guglielmo, M.; De Pasquale, R.; Crisafi, G.; Bisignano, G. Effects of Pteleopsis suberosa extracts on
experimental gastric ulcers and Helicobacter pylori growth. J. Ethnopharmacol. 1998, 59, 167–172. [CrossRef] [PubMed]
143. Aiyegoro, O.A.; Okoh, A.I. Use of bioactive plant products in combination with standard antibiotics: Implications in antimicrobial
chemotherapy. J. Med. Plant Res. 2009, 3, 1147–1152.
144. Khameneh, B.; Iranshahy, M.; Soheili, V.; Fazly Bazzaz, B.S. Review on plant antimicrobials: A mechanistic viewpoint. Antimicrob.
Resist. Infect. Control. 2019, 8, 118. [CrossRef]
145. Eloff, J.N.; Famakin, J.O.; Katerere, D.R.P. Isolation of an antibacterial stilbene from Combretum woodii (Combretaceae) leaves. Afr.
J. Biotechnol. 2005, 4, 1167–1171.
146. Songca, S.P.; Ramurafhi, E.; Oluwafemi, O.S. A pentacyclic triterpene from the leaves of Combretum collinum Fresen showing
antibacterial properties against Staphylococcus aureus. Afr. J. Biochem. Res. 2013, 7, 113–121. [CrossRef]
147. Katerere, D.R.; Gray, A.I.; Nash, R.J.; Waigh, R.D. Antimicrobial activity of pentacyclic triterpenes isolated from African
Combretaceae. Phytochemistry 2003, 63, 81–88. [CrossRef]
148. Pegel, K.H.; Rogers, C.B. The characterization of mollic acid 3ß-D-xyloside and its genuine aglycone mollic acid, two novel
1-α-hydroxycycloartenoids from Combretum molle. J. Chem. Soc. Perkin Trans. 1985, 1, 1711–1715. [CrossRef]
149. Angeh, J.E.; Huang, X.; Swan, G.E.; Möllman, U.; Sattler, I.; Eloff, J.N. Novel antibacterial triterpenoid from Combretum padoides
[Combretaceae]. ARKIVOC 2007, ix, 113–120. [CrossRef]
150. Gossan, D.P.A.; Alabdul Magid, A.; Yao-Kouassi, P.A.; Josse, J.; Gangloff, S.C.; Morjani, H.; Voutquenne-Nazabadioko, L.
Antibacterial and cytotoxic triterpenoids from the roots of Combretum racemosum. Fitoterapia 2016, 110, 89–95. [CrossRef]
[PubMed]
151. Runyoro, D.K.B.; Srivastava, S.K.; Darokar, M.P.; Olipa, N.D.; Cosam, C.J.; Mecky, I.N.M. Anticandidiasis agents from a Tanzanian
plant, Combretum zeyheri. Med. Chem. Res. 2013, 22, 1258–1262. [CrossRef]
152. Spiegler, V.; Sendker, J.; Petereit, F.; Liebau, E.; Hensel, A. Bioassay-guided fractionation of a leaf extract from Combretum
Mucronatum with anthelmintic activity: Oligomeric procyanidins as the active principle. Molecules 2015, 20, 14810–14832.
[CrossRef] [PubMed]
Antibiotics 2023, 12, 264
50 of 52
153. Sun, T.; Qin, B.; Gao, M.; Yin, Y.; Wang, C.; Zang, S.; Li, X.; Zhang, C.; Xin, Y.; Jiang, T. Effects of epigallocatechin gallate on the
cell-wall structure of Mycobacterium smegmatis mc2 155. Nat. Prod. Res. 2015, 29, 2122–2124. [CrossRef] [PubMed]
154. Yamanaka, F.; Hatano, T.; Ito, H.; Taniguchi, S.; Takahashi, E.; Okamoto, K. Antibacterial effects of guava tannins and related
polyphenols on Vibrio and Aeromonas species. Nat. Prod. Commun. 2008, 3, 1934578 × 08003. [CrossRef]
155. Katerere, D.R.; Serage, A.; Eloff, J.N. Isolation and characterisation of antibacterial compounds from Combretum apiculatum
subspecies apiculatum (Combretaceae) leaves. Suid-Afrik. Tydskr. Vir Nat. En Tegnol. 2018, 37, 1–6.
156. Katerere, D.R.; Gray, A.I.; Nash, R.J.; Waigh, R.D. Phytochemical and antimicrobial investigations of stilbenoids and flavonoids
isolated from three species of Combretaceae. Fitoterapia 2012, 83, 932–940. [CrossRef]
157. Pettit, G.R.; Cragg, G.M.; Herald, D.L.; Schmidt, J.M.; Lohavanijaya, P. Isolation and structure of combretastatin. Can. J. Chem.
1982, 60, 1374–1376. [CrossRef]
158. Pettit, G.R.; Singh, S.B. Isolation, structure, and synthesis of combretastatin A-2, A-3, and B-2. Can. J. Chem. 1987, 65, 2390–2396.
[CrossRef]
159. Pettit, G.R.; Singh, S.B.; Niven, M.L.; Hamel, E.; Schmidt, J.M. Isolation, structure, and synthesis of combretastatins A-1 and B-1,
potent new inhibitors of microtubule assembly, derived from Combretum caffrum. J. Nat. Prod. 1987, 50, 119–131. [CrossRef]
160. Pettit, G.R.; Singh, S.B.; Niven, M.L. Antineoplastic agents. 160. Isolation and structure of combretastatin D-1: A cell growth
inhibitory macrocyclic lactone from Combretum caffrum. J. Am. Chem. Soc. 1988, 110, 8539–8540. [CrossRef]
161. Pettit, G.R.; Singh, S.B.; Schmidt, J.M.; Nixen, M.L.; Hamel, E.; Lin, C.M. Isolation, structure, synthesis, and antimitotic properties
of combretastatins B-3 and B-4 from Combretum caffrum. J. Nat. Prod. 1988, 51, 517–527. [CrossRef] [PubMed]
162. Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.; Schmidt, J.M.; Hogan, F. Antineoplastic agents. 291. Isolation and
synthesis of combretastatins A-4, A-5, and A-6. J. Med. Chem. 1995, 38, 1666–1672. [CrossRef] [PubMed]
163. Brookes, K.B.; Doudoukina, O.V.; Katsoulis, L.C.; Veale, D.J.H. Uteroactive constituents of Combretum kraussii. S. Afr. J. Chem.
1999, 52, 127–132.
164. Mushi, N.F.; Innocent, E.; Kidukuli, A.W. Cytotoxic and antimicrobial activities of substituted phenanthrenes from the roots of
Combretum adenogonium Steud Ex A. Rich (Combretaceae). J. Intercult. Ethnopharmacol. 2015, 4, 52. [CrossRef]
165. Malan, E.; Swinny, E. Substituted bibenzyls, phenanthrenes and 9, 10-dihydrophenanthrenes from the heartwood of Combretum
apiculatum. Phytochemistry 1993, 34, 1139–1142. [CrossRef]
166. Letcher, R.M.; Nhamo, L.R.M.; Gumiro, I.T. Chemical constituents of the Combretaceae. Part II. Substituted phenanthrenes and
9,10-dihydrophenanthrenes and a substituted bibenzyl from the heartwood of Combretum molle. J. Chem. Soc. Perkin Trans. 1972, 1,
206–210. [CrossRef]
167. Katerere, D.R.; Graya, A.I.; Kennedy, A.R.; Nash, R.J.; Waigh, R.D. Cyclobutanes from Combretum albopunctatum. Phytochemistry
2004, 65, 433–438. [CrossRef]
168. Dawe, A.; Kapche, G.D.W.F.; Bankeu, J.J.K.; Fawai, Y.; Ali, M.S.; Ngadjui, B.T. Combretins A and B, new cycloartane-type
triterpenes from Combretum fragrans. Helv. Chim. Acta. 2016, 99, 617–620. [CrossRef]
169. Rogers, C.B.; Coombes, P.H. Mollic acid and its glycosides in the trichome secretions of Combretum petrophilum. Biochem. Sys. Ecol.
2001, 29, 329–330. [CrossRef]
170. Araujo, L.C.J.; da Silva, V.C.; Dall’Oglio, E.L.; Teixeira de Sousa, P. Flavonoids from Combretum lanceolatum pohl. Biochem. Sys.
Ecol. 2013, 49, 37–38. [CrossRef]
171. Vandeputte, O.M.; Kiendrebeogo, M.; Rasamiravaka, T.; Stévigny, C.; Duez, P.; Rajaonson, S.; Diallo, B.; Mol, A.; Baucher, M.;
El Jaziri, M. The flavanone naringenin reduces the production of quorum sensing-controlled virulence factors in Pseudomonas
aeruginosa PAO1. Microbiology 2011, 157, 2120–2132. [CrossRef] [PubMed]
172. Pfundstein, B.; El Desouky, S.K.; Hull, W.E.; Haubner, R.; Erben, G.; Owen, R.W. Polyphenolic compounds in the fruits of Egyptian
medicinal plants (Terminalia bellerica, Terminalia chebula and Terminalia horrida): Characterization, quantitation and determination
of antioxidant capacities. Phytochemistry 2010, 71, 1132–1148. [CrossRef] [PubMed]
173. Li, N.; Luo, M.; Fu, Y.; Zu, Y.; Wang, W.; Zhang, L.; Yao, L.; Zhao, C.; Sun, Y. Effect of corilagin on membrane permeability of
Escherichia coli, Staphylococcus aureus and Candida albicans. Phyther. Res. 2013, 27, 1517–1523. [CrossRef] [PubMed]
174. Buzzini, P.; Arapitsas, P.; Goretti, M.; Branda, E.; Turchetti, B.; Pinelli, P.; Romani, A. Antimicrobial and antiviral activity of
hydrolysable tannins. Mini-Rev. Med. Chem. 2008, 8, 1179. [CrossRef]
175. Yoshida, T.; Amakura, Y.; Yoshimura, M. Structural features and biological properties of ellagitannins in some plant families of
the order Myrtales. Int. J. Mol. Sci. 2010, 11, 79–106. [CrossRef]
176. Jossang, A.; Pousset, J.-L.; Bodo, B. Combreglutinin, a hydrolysable tannin from Combretum Glutinosum. J. Nat. Prod. 1994, 57,
732–737. [CrossRef]
177. Moilanen, J. Ellagitannins in Finnish Plant Species–Characterization, Distribution and Oxidative Activity. Doctoral Dissertation,
University of Turku, Turku, Finland, 2015; p. 112.
178. Hattas, D.; Riitta Julkunen-Tiitto, R. The quantification of condensed tannins in African savanna tree species. Phytochem. Lett.
2012, 5, 329–334. [CrossRef]
179. Molino, S.; Casanova, N.A.; Rufián Henares, J.Á.; Fernandez Miyakawa, M.E. Natural tannin wood extracts as a potential food
ingredient in the food industry. J. Agric. Food Chem. 2020, 68, 2836–2848. [CrossRef]
180. Bialonska, D.; Kasimsetty, S.G.; Schrader, K.K.; Ferreira, D. The effect of pomegranate (Punica granatum L.) byproducts and
ellagitannins on the growth of human gut bacteria. J. Agric. Food Chem. 2009, 57, 8344–8349. [CrossRef]
Antibiotics 2023, 12, 264
51 of 52
181. Kuete, V.; Tabopda, T.K.; Ngameni, B.; Nana, F.; Tshikalange, T.E.; Ngadjui, B.T. Antimycobacterial, antibacterial and antifungal
activities of Terminalia superba (Combretaceae). S. Afr. J. Bot. 2010, 76, 125–131. [CrossRef]
182. Hatano, T.; Kusuda, M.; Inada, K.; Ogawa, T.-O.; Shiota, S.; Tsuchiya, T.; Yoshida, T. Effects of tannins and related polyphenols on
methicillin-resistant Staphylococcus aureus. Phytochemistry 2005, 66, 2047–2055. [CrossRef] [PubMed]
183. Shiota, S.; Shimizu, M.; Sugiyama, J.; Morita, Y.; Mizushima, T.; Tsushiya, T. Mechanisms of action of Corilagin and Tellimagrandin
I that remarkably potentiate the activity of beta-lactams against methicillin-resistant Staphyloccus aureus. Microbiol. Immunol. 2004,
48, 67–73. [CrossRef] [PubMed]
184. Shimizu, M.; Shiota, S.; Mizushima, T.; Ito, H.; Hatano, T.; Yoshida, T.; Tsuchiya, T. Marked potentiation of activity of β-lactams
against methicillin-resistant Staphylococcus aureus by corilagin. Antimicrob. Agents Chemother. 2001, 45, 3198–3201. [CrossRef]
185. Taguri, T.; Tanaka, T.; Kouno, I. Antibacterial spectrum of plant polyphenols and extracts depending upon hydroxyphenyl
structure. Biol. Pharm. Bull. 2006, 29, 2226–2235. [CrossRef]
186. Puljula, E.; Walton, G.; Woodward, M.J.; Karonen, M. Antimicrobial activities of ellagitannins against Clostridiales perfringens,
Escherichia coli, Lactobacillus plantarum and Staphylococcus aureus. Molecules 2020, 25, 3714. [CrossRef]
187. Girard, M.; Bee, G. Invited review: Tannins as a potential alternative to antibiotics to prevent coliform diarrhea in weaned pigs.
Animal 2020, 14, 95–107. [CrossRef]
188. Karatoprak, G.Ş.; Küpeli Akkol, E.; Genç, Y.; Bardakcı, H.; Yücel, Ç.; Sobarzo-Sánchez, E. Combretastatins: An overview of
structure, probable mechanisms of action and potential applications. Molecules 2020, 25, 2560. [CrossRef]
189. Pandey, H.; Pandey, P.; Singh, S.; Negi, A.S.; Banerjee, S. Unveiling the future reservoir of anti-cancer molecule—Combretastatin
A4 from callus and cell aggregate suspension culture of flame creeper (Combretum microphyllum): Growth, exudation and elicitation
studies. Plant Cell Tissue Organ Cult. 2020, 143, 681–691. [CrossRef]
190. Schwikkard, S.; Zhou, B.-N.; Glass, T.E.; Sharp, J.L.; Mattern, M.R.; Johnson, R.K.; Kingston, D.G.I. Bioactive compounds from
Combretum erythrophyllum. J. Nat. Prod. 2000, 63, 457–460. [CrossRef]
191. Letcher, R.M.; Nhamo, L.R.M. Chemical constituents of the Combretaceae. Part III. Substituted phenanthrenes, 9,10dihydrophenanthrenes, and bibenzyls from the heartwood of Combretum psidioides. J. Chem. Soc. Perkin Trans. 1972, 1, 2941–2946.
[CrossRef]
192. Pettit, G.R.; Singh, S.B.; Hamel, E.; Lin, C.M.; Alberts, D.S.; Garcia-Kendal, D. Isolation and structure of the strong cell growth and
tubulin inhibitor combretastatin A-4. Experientia 1989, 45, 209–211. [CrossRef]
193. Jain, S.; Nagwanshi, R.; Bakhru, M.; Bageriab, S. Stereoselective photodimerization and antimicrobial activities of heteroaryl
chalcones and their photoproducts. J. Indian Chem. Soc. 2011, 88, 1571–1576.
194. Zhen, J.; Simon, J.E.; Wu, Q. Total synthesis of novel skeleton flavan-alkaloids. Molecules 2020, 25, 4491. [CrossRef] [PubMed]
195. Chinedu, N.P. Qualitative Phytochemical Screening, Anti-inflammatory and Haematological Effects of Alkaloid Extract of
Combretum dolichopetalum Leaves. Asian Hematol. Res. J. 2020, 3, 5–12.
196. Atta-ur-Rahman; Zareen, S.; Choudhary, M.I.; Akhtar, M.N.; Ngounou, F.N. A triterpenoidal saponin and sphingolipids from
Pteleopsis hylodendron. Phytochemistry 2008, 69, 2400–2405. [CrossRef]
197. Kunz, T.C.; Kozjak-Pavlovic, V. Diverse facets of sphingolipid involvement in bacterial infections. Front. Cell Dev. Biol. 2019, 7, 203.
[CrossRef]
198. Natori, T.; Morita, M.; Akimoto, K.; Koezuka, Y. Agelaspins, novel antitumor and immunostimulatory cerebrosides from the
marine sponges Agelas mauritianus. Tetrahedron 1994, 50, 2771–2784. [CrossRef]
199. West-African Herbal Pharmacopoiea. West African Health Organisation (Waho), Bobo-Dioulasso (Burkina Faso); Busia, K., Benjamin,
J.A., Eds.; Ks Printcraft Gh. Ltd.: Kumasi, Ghana, 2013; 260p.
200. West-African Herbal Pharmacopoiea. West African Health Organisation (Waho), Bobo-Dioulasso (Burkina Faso); Okolo, S., Ed.;
Matshidiso Rebecca Moethi: Bobo-Dioulasso, Burkina Faso, 2020.
201. Moshi, A.P.; Matoju, I. The status of research on and application of biopesticides in Tanzania. Review. Crop Prot. 2017, 92, 16–28.
[CrossRef]
202. Stevenson, P.C.; Isman, M.B.; Belmain, S.R. Pesticidal plants in Africa: A global vision of new biological control products from
local uses. Ind. Crops Prod. 2017, 110, 2–9. [CrossRef]
203. Butterweck, V.; Lieflander-Wulf, U.; Winterhoff, H.; Nahrstedt, A. Plasma levels of hypericin in presence of procyanidin B2 and
hyperoside: A pharmacokinetic study in rats. Planta Med. 2003, 69, 189–192. [CrossRef] [PubMed]
204. Cho, J.J.; Kim, H.S.; Kim, C.H.; Cho, S.J. Interaction with polyphenols and antibiotics. J. Life Sci. 2017, 27, 476–481. [CrossRef]
205. Fankam, A.G.; Kuiate, J.R.; Kuete, V. Antibacterial and antibiotic resistance modifying activity of the extracts from Allanblackia
gabonensis, Combretum molle and Gladiolus quartinianus against Gram-negative bacteria including multi-drug resistant phenotypes.
BMC Complement. Altern. Med. 2015, 2015, 15. [CrossRef] [PubMed]
206. Van Vuuren, S.F.; Suliman, S.; Viljoen, A.M. The antimicrobial activity of four commercial essential oils in combination with
conventional antimicrobials. Lett. Appl. Microbiol. 2009, 48, 440–446. [CrossRef] [PubMed]
207. Sun, W.; Sanderson, P.E.; Zheng, W. Drug combination therapy increases successful drug repositioning. Drug Discov. Today 2016,
21, 1189–1195. [CrossRef] [PubMed]
208. Ayaz, M.; Ullah, F.; Sadiq, A.; Ullah, F.; Ovais, M.; Ahmed, J.; Devkota, H.P. Synergistic interactions of phytochemicals with
antimicrobial agents: Potential strategy to counteract drug resistance. Chem. Biol Interact. 2019, 308, 294–303. [CrossRef]
Antibiotics 2023, 12, 264
52 of 52
209. Mabona, U.; Viljoen, A.; Shikanga, E.; Marston, A.; Van Vuuren, S. Antimicrobial activity of southern African medicinal plants
with dermatological relevance: From an ethnopharmacological screening approach, to combination studies and the isolation of a
bioactive compound. J. Ethnopharmacol. 2013, 148, 45–55. [CrossRef]
210. Sorrenti, V.; Randazzo, C.L.; Caggia, C.; Ballistreri, G.; Romeo, F.V.; Fabroni, S.; Timpanaro, N.; Raffaele, M.; Vanella, L. Beneficial
effects of pomegranate peel extract and probiotics on pre-adipocyte differentiation. Front. Microbiol. 2019, 10, 660. [CrossRef]
211. Ahmad, M.H.; Zezi, A.U.; Anafi, S.B.; Alhassan, Z.; Mohammed, M.; Danraka, R.N. Mechanisms of antidiarrhoeal activity of
methanol leaf extract of Combretum hypopilinum diels (combretaceae): Involvement of opioidergic and (α1 and β)-adrenergic
pathways. J. Ethnopharmacol. 2021, 269, 113750. [CrossRef] [PubMed]
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