Ethnopharmacology, Antimicrobial Potency, and Phytochemistry of African Combretum and Pteleopsis Species (Combretaceae): A Review

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.


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-(XDR-TB) 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, 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, 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][13][14][15][16][17][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][20][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].  [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, 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][27][28]. In this review paper, the antimicrobial effects of extracts from various parts and with various polarities from African Combretum and Pteleopsis spp. are  [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][52][53][54][55][56][57][58]80] C. kraussii Hochst syn. C. nelsonii Duemmer Leaf extracts, roots, and leaves Bacterial respiratory diseases and wound healing [22,[81][82][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 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].
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 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].

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]. parts of South Africa in dry forests, savanna woodlands (Brachystegia woodlands), wooded 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 2 C). 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].

Botany
There are nine species of Pteleopsis in tropical Africa [66]. Pteleopsis species are smallto 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 extra-axillary 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].

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

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 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.

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 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).

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][111][112][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 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. MIC    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. 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]

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.
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].

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 CCl 4 , CHCl 3 , 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.

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 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.

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.

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.
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.

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.
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].

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.

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].

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].

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.

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].  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 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 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.

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. [147] 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 acid-3β-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]  [76]
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.

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].

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, 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][150][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.
Antibiotics 2023, 12, x FOR PEER REVIEW 36 o southern Africa and reputed uses for bacterial and fungal infections in traditio medicine, were studied for their antimicrobial triterpenes and triterpenoid glycosi (saponins) ( Table 5). The species that have been studied most frequently are C. imb and C. padoides (syn. C. minutiflorum Exell). Moreover, C. erythrophyllum, C. racemosum vendae, C. zeyheri, C. collinum, C. molle, and C. laxum were also studied in this respect [1 151]. Leaf material was used in most studies, but roots (C. racemosum) and stems (C. laxu have also been used. As not only the leaves, but also the roots and stems of Combret spp. are used for the preparation of herbal remedies for the treatment of infections, th parts of Combretum spp. should also be investigated for their triterpenes. Hydroxylated pentacyclic olean-12-ene triterpene saponins, as well as triterpenoid aglycones, hydroxyimberbic acid, and imberbic acid, were isolated from leaves of C. imberbe (Figure 4). The rhamnose-containing saponins inhibited the growth a number of Gram-positive bacteria but were less active than imberbic acid [147]. Imber acid showed the lowest MIC values of 1.56 and 3.13 µg/mL against Mycobacter fortuitum and S. aureus, respectively. However, all saponins and the imberbic acid w less active against E. coli, with MIC values above 100 µg/mL [147]. Mollic acid and glucosides, including mollic acid-β-D-glucoside, -arabinoside and -xyloside, as wel imberbic acid, were characterized from the leaf trichomes of C. molle and C. petrophi [148,169]. However, according to our literature review, mollic acid and its glucosides h not been tested for their antimicrobial effects; they are foremost known for their go molluscididal effects [169]. Dawe et al. [168] found two new cycloartane-type triterpen combretins A and B, from the leaves of Combretum fragrans (syn. C. adenogonium). An et al. [26] isolated a new antibacterial oleanane-type triterpenoid glycoside from dichloromethane extract of the leaves of C. padoides, namely 1α, 23β-dihydroxyoleanen-29-oic-acid-23β-O-α-4-acetylrhamnopyranoside and 1,22-di-hydroxyoleanen-30-oic acid. Both compounds showed activity against S. aureus and E. coli (w an MIC of 63 µg/mL for both compounds). The pentacyclic triterpene olean-12-ene-3-o isolated from the leaves of C. collinum, was mildly antibacterial against S. aureus and coli (with an MIC of 568.9 µg/mL) [146].

Flavonoids
A number of African Combretum species have been investigated for their flavono and/or the antimicrobial effects of isolated flavonoids (Table 5). Among the most stud

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 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.
Katerere et al. [156] characterized two simple chalcones, cardamomin and 4 -hydroxy-2 ,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 that also quercetin-3-O-galactoside-7-O-rhamnoside-(2→1)-O-β-D-arabinopyranoside was present in the antimycobacterial root extract of C. hartmannianum. 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 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 quorumsensing (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. Kaempferol and the methoxylated quercetin derivatives rhamnocitrin, rhamnazin, and quercetin-5,3′-dimethylether, as well as genkwanin, apigenin, and hydroxy-4′,7dimethoxyflavone, 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′hydroxy-2′,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 that also quercetin-3-O-galactoside-7-O-rhamnoside-(2→1)-O-β-D-arabinopyranoside was present in the antimycobacterial root extract of C. hartmannianum.

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

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 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][176][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-hexahydroxydiphenoyl-D-glucose, and combreglutinin. The ellagitannins were not tested for their antimicrobial effects in this study.
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 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-Shexahydroxydiphenoyl-D-glucose, the characteristic component of many ETs [175][176][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-hexahydroxydiphenoyl-D-glucose, and combreglutinin. The ellagitannins were not tested for their antimicrobial effects in this study. 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 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 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 αand β-punicalagin, isolated from a decoction of Combretum aculeatum, possessed an IC 50 value of 51.48 µM, compared to 6.99 µM for rifampicin. As αand β-punicalagin are not bioavailable, Diop et al. [65] also studied the antibacterial effects of urolithins, the metabolites resulting from the metabolic degradation of αand 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 -di-O-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 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][186][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].

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].

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 alkaloidsthe 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. 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.

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].

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.

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].

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 alkaloidsthe 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.

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].
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.

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.

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]. 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.

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.
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.

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].

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 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].

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.
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.