Biomedicines 11 02605 v3

biomedicines
Review
Potential of Selected African Medicinal Plants as Alternative
Therapeutics against Multi-Drug-Resistant Bacteria
Bertha N. Moiketsi, Katlego P. P. Makale, Gaolathe Rantong, Teddie O. Rahube * and Abdullah Makhzoum *
Department of Biological Sciences and Biotechnology, Faculty of Science, Botswana International University of
Science and Technology (BIUST), Private Bag 16, Palapye, Botswana; [email protected] (B.N.M.);
[email protected] (K.P.P.M.); [email protected] (G.R.)
* Correspondence: [email protected] (T.O.R.); [email protected] (A.M.)
Abstract: Antimicrobial resistance is considered a “One-Health” problem, impacting humans, ani-

mals, and the environment. The problem of the rapid development and spread of bacteria resistant
to multiple antibiotics is a rising global health threat affecting both rich and poor nations. Low-
and middle-income countries are at highest risk, in part due to the lack of innovative research on
the surveillance and discovery of novel therapeutic options. Fast and effective drug discovery is
crucial towards combatting antimicrobial resistance and reducing the burden of infectious diseases.
African medicinal plants have been used for millennia in folk medicine to cure many diseases and
ailments. Over 10% of the Southern African vegetation is applied in traditional medicine, with
over 15 species being partially or fully commercialized. These include the genera Euclea, Ficus,
Aloe, Lippia. And Artemisia, amongst many others. Bioactive compounds from indigenous medicinal
plants, alone or in combination with existing antimicrobials, offer promising solutions towards
overcoming multi-drug resistance. Secondary metabolites have different mechanisms and modes
of action against bacteria, such as the inhibition and disruption of cell wall synthesis; inhibition of
DNA replication and ATP synthesis; inhibition of quorum sensing; inhibition of AHL or oligopeptide
signal generation, broadcasting, and reception; inhibition of the formation of biofilm; disruption
of pathogenicity activities; and generation of reactive oxygen species. The aim of this review is
Citation: Moiketsi, B.N.; Makale, to highlight some promising traditional medicinal plants found in Africa and provide insights
K.P.P.; Rantong, G.; Rahube, T.O.; into their secondary metabolites as alternative options in antibiotic therapy against multi-drug-
Makhzoum, A. Potential of Selected
resistant bacteria. Additionally, synergism between plant secondary metabolites and antibiotics has
African Medicinal Plants as Alternative
been discussed.
Therapeutics against Multi-Drug-
Resistant Bacteria. Biomedicines 2023,
Keywords: antimicrobial resistance; antibiotics; bioactive compounds; secondary metabolites;
11, 2605. https://doi.org/10.3390/
indigenous plants; Africa
biomedicines11102605
Academic Editors: Israa M.S.

Al-Kadmy and Konstantinos Dimas
Received: 30 May 2023

1. Introduction
Revised: 4 September 2023 Antimicrobial resistance (AMR) is a well-recognized global health problem, affect-
Accepted: 18 September 2023 ing both rich and poor nations [1]. AMR is the ability of microorganisms to survive the
Published: 22 September 2023 effects of antimicrobials such as antifungals and antibiotics. Many pathogenic bacteria
have developed resistance to almost all available antibiotics, and even newly developed
antibiotics will ultimately become ineffective against the continuously evolving multi-
drug-resistant (MDR) bacteria [1–3]. Some examples of clinically important MDR bacteria
Copyright: © 2023 by the authors.
are Vancomycin-resistant Enterococci (VRE), Carbapenem-resistant Acinetobacter baumannii
Licensee MDPI, Basel, Switzerland.
(CRAB), Carbapenem-resistant Enterobacteriales (CRE), XDR (extensively drug-resistant)
This article is an open access article
Pseudomonas aeruginosa, extended-spectrum β-lactamase- (ESBL)-producing Enterobacteriales,
distributed under the terms and
and methicillin-resistant Staphylococcus aureus (MRSA) [4–6]. The E. faecium, S. aureus,
conditions of the Creative Commons
Attribution (CC BY) license (https://
K. pneumoniae, A. baumannii, P. aeruginosa, Enterobacter species, and E. coli (ESKAPEE)
creativecommons.org/licenses/by/
acronym is commonly used to refer to highly virulent bacterial pathogens known to
4.0/). “escape” treatment from multiple antibiotics and other traditional treatments [7,8]. The
Biomedicines 2023, 11, 2605. https://doi.org/10.3390/biomedicines11102605 https://www.mdpi.com/journal/biomedicines

Biomedicines 2023, 11, 2605 2 of 30
rapid development and spread of MDR bacteria is a rising One-Health challenge, impacting
humans, animals, and the environment, which means that MDR bacteria and the associated
AMR genes are capable of circulating among different habitats, making them difficult to
control [4,9]. It has been estimated that 10 million deaths will be a result of AMR by the year
2050, and the World Health Organization (WHO) predicts over 24 million people globally
will be condemned to poverty as result of the AMR burden [2]. The European Centre for
Disease Prevention and Control (ECDC) estimates that today AMR is already responsible
for ca. 25,000 deaths and €1.5 billion in health expenditures per year in Europe alone, and
given the limitations of the availability of data, the death toll is estimated to be significantly
higher in Africa, where the expenditure is much higher than in the first-world countries [1].
In fact, the Africa Centres for Disease Prevention and Control (CDC) has urged the public,
academic institutions, farmers, veterinarians, and medical and professional organizations
to become ‘antibiotic guardians’ by cutting the unnecessary use of antibiotics in order to
slow resistance [10,11]. Some bacteria are naturally resistant to antibiotics via mutation and
horizontal gene transfer; however, the frequent use of antibiotics to treat bacterial infections
in healthcare, coupled with anthropogenic activities such as wastewater reuse, among other
agricultural practices, contributes to the rapid spread of antibiotic resistance [2,7].
In low- and middle-income countries (LMICs), there is lack of innovative research on
antibiotic usage, surveillance, and the discovery of novel therapeutic options; therefore, fast
and effective drug discovery is crucial to help reduce the rise of deadly infections, which are
now contributing to more deaths in these countries [12]. Thus, novel efficient antibacterial
agents and alternative strategies are urgently required to fill the void of antibiotic discovery
and development [13]. Medicinal plants have long been used as medicines to treat microbial
infections, among other human diseases; hence, their antibiotic development should now
be focused on, as they have proved to be the best alternatives for novel antibacterial targets
and can be effective against MDR bacteria [3]. Compared to synthetic chemotherapeutic
drugs, natural antibacterial agents and their analogues still dominate the multiple classes of
antibiotics, such as β-lactams, tetracyclines, aminoglycosides, and polypeptides, which are
routinely used in healthcare [13]. These natural antibacterial agents possess advantages in
structural and chemical diversity, accessibility, robust activity, and peculiar modes of action,
and present lower health risks associated with human toxicity or side effects [10,14,15].
Additionally, plants have a superior ability to assimilate genetic information and produce
complex molecules that can be used to make more effective therapeutics. Moreover, there
are significantly lower facility and production costs associated with plant-made drugs, as
it costs significantly less to grow plants and mass-produce pharmaceutical compounds,
which can allow more capital to be invested into the research and development of new ther-
apeutics. Research focusing on plant secondary metabolites and their possible effectiveness
against antibiotic-resistant bacteria could lead to much anticipated discoveries in terms of
drug development.
In this paper, we highlight some promising traditional medicinal plants found in the
African continent, review the current literature and studies on the therapeutic potential
of traditional medicinal plants, and provide insights into their secondary metabolites and
modes of action as alternative options in antibiotic therapy against MDR bacteria.
2. Materials and Methods

A comprehensive literature search was conducted on MDR bacteria of clinical rele-
vance, along with their associated resistance mechanisms. A total of 36 selected medicinal
plants indigenous to the continent of Africa were selected (refer to Figure 1). They were
also reviewed together with their associated secondary metabolites known to have poten-
tial antibacterial properties and their modes of action. The reviewed literature included
conference papers, books, theses, and papers published in peer-reviewed international
journals, as well as reports from international, regional, and national organizations. The
PubMed and Scopus databases, as well as the Google Scholar search engine, were used in
mining the literature using the following keywords alone or in combination: muti-drug-

organizations. The PubMed and Scopus databases, as well as the Google Scholar search
engine, were used in mining the literature using the following keywords alone or in
combination:
resistant muti-drug-resistant
bacteria; bacteria; plant
plant bioactive compounds; bioactive
plant compounds;
secondary plantindigenous
metabolites; secondary
metabolites; indigenous plants; Africa. There was no restriction on the year of publication
plants; Africa. There was no restriction on the year of publication of the selected literature;
of the
the selected literature;
information the information
in this article in in
was collected this article was from
publications collected
bothin publications
original from
and review
both original and review articles
articles spanning from 1994 to 2023. spanning from 1994 to 2023.
Figure 1.
Figure 1. Diverse
Diverse plant
plant species
species with
with potential
potential antimicrobial
antimicrobial properties
properties widely
widely distributed
distributed across
across
different regions in Africa: (A–F) examples of plant species that have been commercialized
different regions in Africa: (A–F) examples of plant species that have been commercialized as as
treatment for bacterial infections. See the Supplementary Materials (Table S1) for more details about
treatment for bacterial infections. See the Supplementary Materials (Table S1) for more details about
species origins, studies, and sources.
3. Results
3. Results and
and Discussion
Discussion
3.1. Clinically Important Multi-Drug-Resistant
Multi-Drug-Resistant Bacteria
Bacteria and
and Modes
Modes of
of Antibiotic
Antibiotic Resistance
Resistance
Antibiotic resistance is found
found inin both
both Gram-negative
Gram-negative and and Gram-positive
Gram-positive strains
strains ofof
bacteria, which are leading causes of hospital- and community-acquired
which are leading causes of hospital- and community-acquired infections, infections, rang-
ing fromfrom
ranging common
common infections such
infections as skin
such as skinandandsoft
softtissue
tissueinfections
infectionsto to life-threatening
life-threatening
infections [4]. MDRMDR bacterial
bacterial infections
infections account
account forfor millions
millions of of global
global deaths
deaths annually,
with
with over 40%40% being
beingneonatal
neonataldeaths
deathsand andwith
with that
that percentage
percentage expected
expected to increase
to increase in
in the
the absence
absence of effective
of effective therapeutic
therapeutic drugs drugs [4]. Gram-negative
[4]. Gram-negative bacteria
bacteria belonging
belonging to theto the
order
order Enterobacteriales
Enterobacteriales have have
sincesince developed
developed resistance
resistance mechanisms
mechanisms posing
posing a serious
a serious threat
threat to
to human health, especially in hospitals and nursing homes [4,7,16]. Enterobacter
human health, especially in hospitals and nursing homes [4,7,16]. Enterobacter species are species
are
alsoalso Gram-negative
Gram-negative andandare are characterized
characterized as facultatively
as facultatively anaerobic,
anaerobic, rod-shaped
rod-shaped bac-
bacteria
teria the Enterobacteriales
of theofEnterobacteriales family,family,
whichwhich
includesincludes E. coli
E. coli and and K. pneumoniae
K. pneumoniae [17]. This[17].
group This
of
group
pathogensof pathogens are a major
are a major cause cause of urinary
of urinary andand respiratorytract
respiratory tractinfections,
infections, causing
causing
bacteremia
bacteremia and and pneumonia
pneumonia in in the
the immunocompromised
immunocompromised [17,18]. [17,18]. Acinetobacter
Acinetobacter species
species
(e.g., A. baumannii) are Gram-negative, aerobic, non-fermenting,
(e.g., A. baumannii) are Gram-negative, aerobic, non-fermenting, non-fastidious, non-fastidious, ubiqui-
tous coccobacillus,
ubiquitous or pleomorphic
coccobacillus, bacteria,
or pleomorphic and are
bacteria, and responsible for bloodstream
are responsible for bloodstream infec-
tions and ventilator-associated pneumonia [17,18]. Acinetobacter species
infections and ventilator-associated pneumonia [17,18]. Acinetobacter species have the have the ability
to resisttodesiccation
ability and form
resist desiccation andbiofilms, and the
form biofilms, andpresence
the presenceof fundamental
of fundamental virulence fac-
virulence
tors, such
factors, as as
such secretion
secretionsystems,
systems, surface
surfaceadhesins,
adhesins,and andglycoconjugates,
glycoconjugates,aggravate
aggravate theirtheir
pathogenicity [19,20]. Pseudomonas aureginosa, is an example of another Gram-negative bac-
terium that causes urinary tract infections, surgical site infections, pneumonia, septicemia,
and bacteremia, especially in immunocompromised individuals [21]. P. aeruginosa displays

innate resistance to a wide array of antibiotics. It is resistant to a wide spectrum of antibiotic
classes, including penems and β-lactam, and its resistance to fluroquinolones is due to its
ability to mutate on DNA gyrase or topoisomerase [21,22]. P. aeruginosa employs a variety of
mechanisms such as alterations in porin channels, efflux pumps, targets modifications, and
β-lactamases to exert resistance to antimicrobial agents [21–23]. A. baumannii, P. aeruginosa,
and several members of the Enterobacteriales family exhibit broad resistance to carbapenems
antibiotics; hence, at the top of the WHO priority list is research and development for new
antibiotics, which are urgently needed [17,24].
The Gram-positive bacteria of clinical concern include the genera Bacillus (e.g., Entero-
coccus species, Staphylococcus aureus), Clostridium (C. botulinum, C. perfringens), Listeria
(L. monocytogenes), Gardenella (G. vaginalis), and Corynebacterium (C. diphtheriae) [24].
Enterococcus faecalis is an enterococcal bacterium that is responsible for infections in
the gut of humans, and is known to cause severe infections in immunocompromised
individuals [13,16]. VRE readily accumulate mutations and exogenous genes (VanA, VanB,
VanD, VanE, VanG, VanL) that confer resistance to vancomycin, including other antibiotics
classes such as β-lactam [25,26]. S. aureus is a Gram-positive spherical bacterium that is
normal microflora of the skin and the nasal mucosa, which can also be pathogenic [27,28].
Pathogenic strains of S. aureus normally cause life-threatening soft tissue abscesses, pneu-
monia, septicemia, and bacteremia, and can cause infections from contaminated medical
implants. Its ability to form biofilms also poses a challenge in antibiotics-mediated treat-
ments [29]. Additionally, due to the secretion of the TSST-1 exotoxin in some strains,
S. aureus can also cause toxic shock syndrome [30,31]. S. aureus has evolved to develop
resistance to vancomycin, methicillin, and many β-lactam classes of antibiotics [31]. MRSA
harbors a mecA gene on the staphylococcal cassette chromosome mec (SCCmec) and codes
for PBP2a [32]. A protective protein bound to the ribosomes of the bacterial cell inactivates
the antibiotics via ‘target alteration’ by altering their structural confirmation [33].
The general mechanisms of antibacterial resistance range from alterations of binding
sites, alterations of the bacterial porins’ structure, antibiotics efflux through the bacterial
efflux pump structure, and destruction of antibacterial agents by hydrolytic enzymes [5,16].
Additionally, MDR bacteria can resist antibiotics via one mechanism or by combining
more than one to produce their multiple resistance to antibiotics and other antimicrobials,
including disinfectants and heavy metals in personal care products [7]. The examples of
clinically relevant bacteria and their modes of action are summarized in Table 1.
Table 1. Mechanisms of antibiotic resistance to common classes of antibiotics using healthcare.
Bacterial Strain Antibiotics Mechanism of Resistance Reference

Altered membrane permeability.
A. baumanni β-Lactams, aminoglycosides, carbapenems Enzyme inactivation by [4,6,8]
aminoglycoside-modifying enzymes
Tetracycline, gentamycin,
E. coli AcrAB-TolC efflux pump [5,8]
amoxicillin, trimethoprim
Production of inactivation enzymes using
extended-spectrum β-lactamases,
Enterobacter species β-lactams, most antibiotics, carbapenem [13,16]
carbapenemase acetyltransferases,
phophotransferases, and adenyltransferase
Changes in membrane permeability
Third-generation cephalosporins, Alterations of target site
K. pneumoniae [9,34]
carbapenem, β-lactams Efflux pump
Enzyme inactivation by β-lactamases
NorA efflux pumps
Cephalosporins, methicillin, oxacillin,
S. aureus Mutations in genes involved in cell wall synthesis [13,16]
peniccilin, vancomycin, erythromycin
Alterations of antibiotic binding site
Table 1. Cont.
Bacterial Strain Antibiotics Mechanism of Resistance Reference

Structural changes in the cell’s surface casings
Decreases in antibiotic porins
Penem groups of antibiotics, MexAB-OprMM efflux pump
P. aeruginosa [5,16]
β-lactams, fluoroquinolones Enzyme inactivation by β-lactamases
Delay of the incoming flow by modifying the
structure of the antibiotic
3.2. Diversity and Distribution of African Medicinal Plants with Potential Antimicrobial Properties
Thirty-six promising medicinal plant species are highlighted in this review. They are
widely distributed across the African region. Southern Africa has the majority, followed
by East Africa, then Central Africa, while West Africa and North Africa have the least
(Figure 1). Hibiscus calyphyllus is common to all the regions; Cassia abbreviata, Dicoma anomala
Sond, and Securidosa longipendunculata are also found in all the regions except North Africa.
Dichrostachys cinerea is also universal to all regions except West Africa. Fifteen species (Adansonia
digitata, Aloe zebrina Baker, Aloe ferox, Artemisia afra, Boscia albitrunca, Colophospermum
mopane, Combretum hereroense, Commiphora glandulosa, Cynodon transvaalensis, Euclea undulata,
Harpagophytum procumbens, Hirpicium bechuanense, Lippia javanica, Ozoroa paniculosa,
Sanseviera scabrifolia, Sclerocarya birrea) were found to be unique to the Southern African
region, nine (Elephantorhiza goetzei, Grewia bicolor, Grewia flava, Harpagophytum procumbens,
Lippia scaberrima, Mimusopus zeyheri, Myrothamnus flabellifolius, Scadoxus puniceus,
Terminalia sericea) are common to Southern and East Africa, and two (Capparis tomentosa,
Laphangium luteoalbum) are found only in Southern and North Africa. Asparagus africanus,
Vanguera infausta, Ximenia americana, and Ximenia caffra were found to be distributed in
Central, East, and Southern Africa.
Over 10% of the Southern African vegetation is applied in traditional medicine, with
over 15 species being partially or fully commercialized, which can be found in local
pharmacies. These include Hibiscus calyphyllus, Harpagophytum procumbens, Cassia abbreviata,
Aloe ferox, Lippia javanica, and Artemisia afra, amongst many others (Figure 1) [35–40].
C. abbreviata, which is also known as long-tail Cassia (or Monepenepe in Setswana, a native
language of Botswana), belongs to the Caesalpiniaceae family and is characterized by thick
bushes, brown bark, a rounded crown, yellowish leaves, and sweet-scented flowers, as
well as long cylindrical dark brown fruits hanging in pods (Figure 1) [41]. The sun-dried
bark is boiled in water and served as a hot tea to individuals with miscellaneous stomach
ailments, skin problems, and STIs [38] (Table 2). H. calyphyllus, described as a large yellow
hibiscus (or Motsididi in Setswana), is a leafy shrub with wide and simple serrate leaves
and yellow flowers with a dark red center (Figure 1), belonging to the Malvaceae family [40].
The flowers, which have been reported to be rich in flavonoids and phenolic acids, are
traditionally sun-dried, boiled, and served as a hot beverage to treat intestinal ailments
in many sub-tropical parts of Africa [40,42] (Table 2). A. afra, also known an African
wormwood, belongs to the Asteraceae family [43]. It is an erect, perennial woody shrub
with oval-shaped, greyish-looking leaves (Figure 1). The leaves, stems, and roots are rich
in terpenoids, tannins, saponins, and glycosides, which are active against colds, coughs,
influenza, sore throat, malaria, asthma, pneumonia, and diabetes [44]. These parts of the
plants are served pulverized as a hot beverage [45] (Table 1).
L. javanica (lemon bush), of the family Verbenaceae, is a woody shrub with aromatic
leaves that gives a lemon-like smell, which is used as a culinary spice, as well as to
treat coughs, colds, fever, chest ailments, kidney stones, measles, rashes, and stom-
ach problems [37,46]. Small, dense spikes of white flowers are borne in the axils of
leaves (Figure 1). Dried lemon bush leaves are boiled and consumed as is or applied on
affected areas [47].
H. procumbens of the sesame seed or Pedaliaceae family, popularly known as devil’s

claw, is rich in terpenoids, iridoid glycosides, glycosides, and acetylated phenolic com-
pounds [47]. It is a tuberous perennial plant with creeping stems and dark pink flowers
(Figure 1). Devil’s claw is used for a wide variety of health conditions in the form of hot
or cooled infusions, decoctions, tinctures, powders, and extracts to treat blood diseases,
urinary tract infections, postpartum pains, sprains, sores, sexually transmitted diseases,
ulcers, and boils [48]. Commercially, the secondary tubers or roots are pulverized into
capsules [47] (Table 2).
Aloe ferox (Xanthorrheaceae, previously Asphodelaceae, Aloaceae, or Liliaceae; commonly
known as the bitter aloe in English and kgwaphane or mokhwapha in Setswana) is a
cherished, popular, ornamental single-stemmed plant with erect racemes of red, orange,
yellow, or rarely white flowers, with spreading or gracefully curved thorny leaves
(Figure 1) [49,50]). Traditionally, the fresh leaf is cut up, the flesh is extracted and directly
applied on the affected areas, and it is consumed as is or diluted in cold water [39]. Com-
mercially, it is incorporated into different cosmetic products, health drinks, foods, and
beverages to deal with various ailments [50] (Table 2). B. albitrunca is a medium-sized ever-
green tree belonging to the Capparaceae or Caper family and is served as hot coffee or tea [51].
The bark, leaves, and roots are mainly used as herbal medicines for STIs and skin and
stomach infections [51]. In fact, in a study by Pendota et al. in 2015, crude, dichloromethane,
ethyl acetate, and butanol leaf extracts were evaluated and confirmed for antibacterial
activities against B. subtilis, S. aureus, E. coli, and K. pneumoniae. Motlhanka et al. conducted
a study to assess the antibacterial properties from the resin of C. glandulosa. This is a
single-stemmed tree with greyish-green to yellowish-green flaking bark that belongs to the
family Burseraceae [52]. Crude aqueous and chloroform extracts of the stem resin, as well as
the isolated compound, exhibited good in vitro antibacterial activity against Gram-positive
bacteria, B. subtilis, C. perfringens, and S. aureus, as well as multi-drug-resistant S. aureus,
XU212-tetracycline-resistant, and SA1199B-norfloxacin-resistant strains [47].
X. caffra (Ximeniaceae), commonly known as “sour plum”, is traditionally used both
topically and orally to treat a wide range of bacterial infections such as wounds, STIs,
respiratory ailments, digestive tract ailments, colds, and coughs [53,54]. Phytochemical
investigations of the bark, fruits, leaves, roots, and seeds of the sour plum revealed various
compounds, including flavonoids, phenols, phytosterols, and tannins as active compounds
against bacterial pathogens [55]. The methanol extracts of X. caffra roots exhibited an-
tibacterial activities against S. aureus and S. epidermidis [56]. D. cinerea is a thornbush
belonging to the Leguminosae subfamily Mimosoideae. It is a medicinal plant that is native
to Africa and rich in tannins in its leaves, bark, and roots [57,58]. Tannins were isolated from
D. cinerea and assayed against S. aureus, S. boydii, S. flexneri, E. coli, and P. aeruginosa using
the agar diffusion method [57]. The associated tannins exhibited antibacterial activities
against all test microorganisms. This explains why the dried bark, roots, and leaves are
served as a hot tea to traditionally treat sexually transmitted, respiratory, dental, skin, and
intestinal infections [58].
In a study aimed at investigating the in vitro antimicrobial activity of ethanolic extracts
of seventeen species of Sansevieria, including S. scabrifolia, against E. coli using the agar disk
diffusion method, a degree of inhibition was found [35]. The leaves of this species are used
to treat ear infections, toothache, and diarrhea [54].
C. tomentosa (belonging to the family Capparaceae) is a scrambling shrub that grows
as high as 10 m tall and is found across North Africa and Southern Africa (Table 2). It
is used to treat pneumonia, coughs, headaches, tuberculosis, and gonorrhea [59]. The
associated phytochemicals that are extracted from the hairy yellow-green twigs and leaves
are linked to its unique biological, bactericidal, and bacteriostatic activities, which include
alkaloids, L’stachydrine, saponin glycosides, phytosterols, terpenoids, tannins, and anthra-
noids [59]. Studies have shown that this species has good antimicrobial activity against
antibiotic-resistant S. aureus, S. pyogenes, E. coli, and P. aeruginosa [60]. O. paniculosa (Anacar-
diaceae) is an evergreen, semideciduous, small- to medium-sized single-stemmed tree that
is rich with phenols [61]. Phenolic-enriched leaf extracts of O. paniculosa were prepared
using a mixture of 1% HCl-acidified 70% acetone and n-hexane, and then tested against
S. aureus, P. aeruginosa, E. coli, and E. faecalis [61]. These extracts had good activities relat-
ing to diarrhea mechanisms or pharmacological relevance. E. undulata (belonging to the
Ebenaceae or Ebony family) has egg-shaped to wide, bluntly pointed waxy leaves, yellowish
fragrant flowers, and globose fleshy fruits that are all traditionally used for the treatment
of body pains, chest complaints, cough, diarrhea, headaches, heart disease, and tooth
aches because of their wealth of diterpenes, flavonoids, naphthoquinones, phytosterols,
saponins, and tannins [62]. In a previous study, the antimicrobial activity of E. undulata
chewing sticks against multi-drug-resistant S. mutans was determined [63]. The minimum
inhibitory concentrations ranged from 0.385 to 11.22 mg/mL and the minimum bactericidal
concentrations from 0.485 to 20.20 mg/mL. T. sericea (of the family Combretaceae) is a small
to medium deciduous rounded flowering shrub whose roots are traditionally used to treat
diarrhea, skin rashes, tuberculosis, and opportunistic infections associated with HIV/AIDS
in Botswana [64]. It has been reported that dichloromethane/methanol (1:1) extracts of
the stems, bark, leaves, and roots have antibacterial activity against B. subtilis, B. cereus,
S. aureus, E. coli, K. pneumoniae, P. aeruginosa, S. sonnei, S. typhimurium, and S. epidermidis [65].
The compounds isolated from this species so far include a triterpene sericoside, resveratrol-
3-O-β-D-rutinoside, and hydroxystilbene glycoside [66].
S. scabrifolia (also known as Mosokelatsebeng in Setswana) is a stemless evergreen
perennial succulent that grows from a thick rhizome. Its fleshy leaves are warmed in a
fire and the juice is squeezed into the ear or tooth to treat ear infections and cavities in
Botswana [54]. In Namibia, the leaf sap is applied to wounds to prevent infection and
accelerate healing [67]. This bactericidal capacity was also confirmed by Tkachenko et al.,
showing that the crude extracts had antibacterial activity against pathogenic E. coli [67].
The antibacterial activity in the Sansevieria genus may be due to the presence of alkaloids,
saponins, terpenoids, steroids, glycosides, and tannins [65].
Table 2. Summary of African medicinal plants, their uses in folk medicine, and their geographical
locations.
Setswana Name Manner of Distribution in

Scientific Name Ailments Treated References
(Common Name) Administration Africa
Fruit is added to milk and Mozambique
consumed as is.
Seeds are crushed and the Intestinal infections, Namibia
Mowana oil is extracted.
Adansonia digitata respiratory infections, [68]
(African baobab) Bark, flowers, leaves, and skin infections
roots are pulverized and South Africa
consumed as a hot beverage
Angola
Kgophane/ Leaf flesh is cut up and Namibia
Aloe zebrina
Mokhgwapha juice extracted to be applied Skin infections, STIs Mozambique [39]
Baker/Aloe ferox
(variegated aloe) as is or diluted in water Zambia
Zimbabwe
Eswatini
Dried tubers or roots are Lesotho
Mhalatsamaru/wild Genital sores
Asparagus africanus boiled and served as Mozambique [47]
Asparagus and wounds
a beverage Namibia
Zimbabwe
Cameroon
Chad
Ethiopia
Leaves, stems, and roots are Respiratory infections Kenya
Lengana
Artemisia afra boiled in water and and related symptoms Namibia [45]
(African woodworm)
served hot such as fevers Tanzania
Uganda
South Africa
Zimbabwe
Table 2. Cont.

Eswatini
Mozambique
Motopi Pulverized leaves are
Boscia albitrunca Respiratory infections South Africa [69]
(Shepherd’s tree) served in warm milk Zambia
Zimbabwe
Tropical Africa
Motawana Dried bark, stems, leaves, Namibia
Respiratory system
Capparis tomentosa or roots are boiled and [38]
(African caper) infections, STIs Mozambique
consumed as tea South Africa
DRC
Eswatini
Kenya
Mozambique
Monepenepe Sun dried bark or stem is Namibia
Diarrhea, skin diseases,
Cassia abbreviata boiled in water and [38]
(long pod cassia) STIs, stomach infections Somalia
served hot South Africa
Tanzania
Zambia
Zimbabwe
Pulverized seeds are boiled Angola
and orally administered Malawi
Mophane Gum from the stem is Stomach infections, Mozambique
Colophospermum mopane [52]
(mopane tree) applied on affected areas. STIs, sore eyes Namibia
Roots are boiled to make a Zambia
hot beverage Zimbabwe
Eswatini
Fruits are eaten as is. Mozambique
Mokabi
Combretum hereroense Dried leaves are boiled to Stomach infections Namibia [47]
(russet bushwillow)
make tea South Africa
Zimbabwe
Several incisions are made Angola
to the plant during winter, Mozambique
Moroka (tall common and the resinous exudate is Skin and soft Namibia
Commiphora glandulosa [70]
corkwood) harvested and applied to tissue infections South Africa
affected areas.
Zambia
The bark is boiled and
consumed as tea Zimbabwe
Angola
Eswatini
Lesotho
Ground roots
Malawi
Monamane and root bark are sun-dried
Cynodon transvaalensis Stomach infections, fever Mozambique [47]
(Burtt-Davy) and pulverized for
Namibia
beverage preparation
South Africa
Zambia
Zimbabwe
Dried bark, roots, and
leaves are boiled to make
STIs,
the beverage. From Eastern Cape
Moselesele intestinal infections,
Dichrostachys cinerea Seeds are crushed to extract RSA to Tropical [57]
(sickle bush) dental infections,
the oil. East Africa
skin infections
Incisions on the stem are
made to collect gum
Angola
Burundi
DRC
Tlhonya Dried roots are boiled in Stomach infections Rwanda
Dicoma anomala Sond. [71]
(fever/stomach bush water and served as tea and diarrhea South Africa
Tanzania
Zambia
Zimbabwe
Table 2. Cont.

Malawi
Mozambique
Mositsane/Mosidi Intestinal infections, Namibia
Bark and root decoctions
Elephantorhiza goetzei (large been urinary tract infections, South Africa [72]
are taken orally
elephant root) STIs Tanzania
Zambia
Zimbabwe
The roots directly brush the Namibia
teeth and mouth. Mouth sores
Motlhakola Pulverized leaves make a and wounds, Swaziland
Euclea undulata hot beverage for tooth ache and [62]
(common guarri)
oral ingestion. sore throat,
intestinal infections Zimbabwe
Bark is boiled and served as
hot tea
Fruit is eaten or prepared Angola
Grewia bicolor; Moretlwa/Mogwana into a dry pulp. Cavities Eswatini
Grewia flava; (wild currant/velvet Fresh or dry roots are Urinary tract infections, Ethiopia [73]
Grewia flavescens raisins/brandy bush) boiled to prepare skin infections Namibia
a beverage Zimbabwe
Angola
Sun-dried secondary tubers Namibia
Sengaparile/
Harpagophytum or roots are pulverized into Intestinal infections, South Africa
Lengakapitsi [47]
procumbens capsules for kidney infections Mozambique
(devil’s claw)
average preparation Zambia
Zimbabwe
Sun-dried flowers are West, North, East and
Motsididi (Wild
Hibiscus calyphyllus boiled in water and served Stomach infections some parts of [42]
Hibiscus/Roselle)
hot or cold Southern Africa
South Africa
Kgalemela Dried tubers or roots are
Hirpicium bechuanense Infections and diarrhea Mozambique [42]
(S. Moore-Rossler) boiled and consumed as tea Zimbabwe
Fruit is consumed fresh or Eswatini
as a dry pulp.
Mouth wounds,
Mompudu Pulverized flowers are used Mozambique
Mimosopus zeyheri Dental infections, [74]
(red milkwood) to make snuff.
STIs,
Dried bark, leaves, and
soft tissue infections South Africa
roots are boiled and served
as tea
Angola
DRC
Kenya
Tanzania
Lesotho
Kgomodimetsing Leaves are pulverized to Respiratory infections,
Myrothamnus flabellifolius Malawi [75]
(resurrection plant) make a hot beverage soft tissue infections Mozambique
Namibia
South Africa
Zambia
Zimbabwe
Sun-dried bark, stems, Namibia
Monokane leaves, or roots are
Ozoroa paniculosa (bushveld ozoroa/ Fevers associated South Africa [47,76]
pulverized for beverage with infections
common resin tree) preparation Zimbabwe
Namibia
Fleshy leaves are warmed Mozambique
Mosokelatsebeng
Sanseviera scabrifolia in a fire and the juice is Ear infections South Africa [53,67]
(bowstring hemp)
squeezed into the ear Zambia
Zimbabwe
Biomedicines 2023, 11, 2605 10 of 30
Table 2. Cont.

Eswatini
Ethiopia
Lesotho
Dried tubers or roots are Malawi
Mathubadifhala
Scadoxus puniceus boiled and served as tea or Wound infections Mozambique [77]
(blood lily)
applied on affected areas South Africa
Tanzania
Zambia
Zimbabwe
Angola
Fruit is eaten as is Eswatini
Stem or bark is boiled in Malawi
water and served hot Skin infections Mozambique
Sclerocarya birrea Morula/Marula [47]
or cold. Mouth wounds Namibia
Seeds are crushed to extract South Africa
the oil for skin application Zambia
Zimbabwe
Dried stem bark and roots
are boiled and orally
Skin infections,
Securidosa administered. Tropical and
Mmaba (violet tree) respiratory infections, [78]
longipenduculata Pulverized bark makes a Subtropical Africa
urinary tract infections
paste and is applied to
affected areas
Angola
Leaves and roots are boiled DRC
and consumed as tea. Respiratory infections, Mozambique
Mogonono
Terminalia sericea Pulverized leaves are intestinal infections, Namibia [79]
(silver cluster-leaf)
applied as a paste on soft tissue wounds South Africa
affected area Tanzania
Zimbabwe
Kenya
Madagascar
Malawi
Fruit is eaten fresh or dry.
Mouth wounds, Mozambique
Seeds are eaten as they are.
Vanguera infausta Mmilo (wild medlar) respiratory infections, Namibia [80]
Root and leaves are boiled
intestinal infections South Africa
and orally administered
Tanzania
Uganda
Zimbabwe
Angola
Dried and crushed leaves Lesotho
Moretologa wa are boiled in water for oral Malawi
Ximenia administration. The water Body sores, STIs,
pudi/moretologa Mozambique [54]
americana/Ximenia caffra extracts are applied on diarrhea, sore eyes
wa kgomo South Africa
direct sores. The fruit is Swaziland
eaten as is Tanzania
3.3. Plant Secondary Metabolites with Antimicrobial Potential

Plants are known to synthesize and produce diverse groups of organic compounds that
are involved in assorted metabolically related functions of the plant, known as secondary
metabolites [81]. Their primary function to the plants is in the interaction of the plant
with the environment, and they are mostly released in response to abiotic and biotic
stresses, thereby supporting plant survival as molecules of defenses [82]. Examples of
classes of secondary metabolites include terpenoids, phenols, and derivatives, as well as
glucosinolates and alkaloids [83,84].
3.3.1. Alkaloids
Alkaloids are nitrogenous compounds that can be classified as natural, semi-synthetic,
and synthetic or based on their chemical structure into typical alkaloids with a heterocyclic
glucosinolates and alkaloids [83,84].
3.3.1. Alkaloids
Alkaloids are nitrogenous compounds that can be classified as natural, semi-
Biomedicinessynthetic,
2023, 11, 2605
and synthetic or based on their chemical structure into typical alkaloids with 11 a
of 30
heterocyclic ring or atypical alkaloid non-heterocyclic ring [5]. Additionally, they may be
split into several classes: tropanes, indole, purines, imidazole, pyrrolidine, pyrrolizidine,
ring or atypical alkaloid non-heterocyclic ring [5]. Additionally, they may be split into
isoquinoline, piperidine, and quinolizidine
several classes: tropanes, indole,[85]. The imidazole,
purines, antibacterial capacity
pyrrolidine, of alkaloids
pyrrolizidine, has
isoquino-
been documentedline,andpiperidine,
has been linked to efflux pump
and quinolizidine [85]. Theinhibition, bacterial
antibacterial capacitycell
of wall synthesis
alkaloids has been
inhibition, changes in cell membrane
documented and has beenpermeability, inhibition
linked to efflux of bacterial
pump inhibition, metabolism,
bacterial and
cell wall synthesis
nucleic acid and protein synthesis [85,86]. For example, strychnine from C. tomentosa hasand
inhibition, changes in cell membrane permeability, inhibition of bacterial metabolism,
nucleic acid and protein synthesis [85,86]. For example, strychnine from C. tomentosa
antibacterial activity against E. coli, P. aeruginosa, and K. pneumoniae (Table 3). Other plant-
has antibacterial activity against E. coli, P. aeruginosa, and K. pneumoniae (Table 3). Other
associated alkaloids include nicotine,
plant-associated ephedrine,
alkaloids morphine,
include nicotine, and quinine
ephedrine, morphine,(Figure 2). (Figure 2).
and quinine
Figure 2. ExamplesFigure 2. Examples of plant-associated

of plant-associated alkaloids. alkaloids.
3.3.2. Polyphenols
Polyphenols are a large group of secondary metabolites that are classified according to
their phenolic groups and structural elements as flavonoids, stilbenes, lignans, tannins, and
phenolic acids [87]. The antibacterial capacity levels of polyphenols towards Gram-negative
and positive MDR bacteria have been linked to their ability to bind to bacterial enzymes
via a hydrogen bond, inducing several modifications in cell membrane permeability and
cell wall integrity [86,88,89]. Examples include catechin from Adansonia digitata and vitexin
from tannic acid from Dichrostachys cinerea (see Table 3). Tannin is a descriptive name for a
group of polymeric phenolic substances capable of tanning leather or precipitating gelatin
from solution [57].
3.3.3. Terpenes
Terpenes are a large group of hydrocarbons synthesized from the 5-carbon precursor
units of isopentenyl pyrophosphate and its functional isomer dimethylallyl pyprophos-
phate [90]. According to the number of isoprenes, they are classified into monoterpenes
(e.g., limonene from A. afra (Table 3)), diterpenes (e.g., retinol), triterpenes (e.g., oleanolic
acid from the Hibiscus spp.), and tetraterpenes (e.g., lutein, brassicasterol, campesterol, and
β-sitosterol from Artemisia) [35,91,92] (Figure 3). The broad antibacterial activity of the
terpenes includes efflux pump inhibition and the inhibition of bacterial growth and mem-
brane properties towards MDR bacteria E. coli, S. aureus, and Enterobacter species [91,93,94]
(see Table 3).
Bark,
Catechin
Ximenia fruit,
Gallic acid E. coli
americana/Ximenia roots, [53,55]
Quercetin P. aeruginosa
Biomedicines 2023, 11, 2605 caffra seeds, 12 of 30
Proanthocyanidin
leaves
Chemicalstructures
Figure3.3.Chemical
Figure structuresof
ofplant-associated
plant-associatedterpenes.
terpenes.
Table 3. Studied secondary metabolites from selected African medicinal plants with antimicrobial
3.4. Therapeutic Potential of Traditional Medicinal Plants against MDR Bacteria
properties against MDR bacteria.
Antibiotics are definitely the cornerstones of modern medicine; unfortunately, we are
still experiencing the rapid
Plant Part spread of foodborne pathogens,MDR
Active Compound
Bacteria of antibiotic-
emergence Reference
Active Against
resistant microbial strains, and increasing failure of available chemotherapeutics [108].
E. coli
Hence, there is a need for efficient antibacterial
Leaves,
Rutin agents to fill the gap for the discovery and
E. aerogenes
Catechin
development
Adansonia digitataof anti-MDR
stems, agents. Natural products dominate the preferred chemical
K. pneumoniae [95]
Gallic acid
roots
scaffolds for the discovery of antibacterialCaffeic agents P. aeruginosa
[13]. In fact, in Africa, traditional healers,
acid
S. aureus
herbalists, and individuals have used a variety of wild leaves, roots, barks, fruits, and
E. coli
seeds to combat miscellaneous
Aloe zebrina
bacterialStearic
Leaves, roots,
illnesses
acid
and diseases [109]. Medicinal plants
K. pneumoniae
have a wide array of phytochemicals, alkaloids, phenolics, polyphenols, [96]
flavonoids,
Baker/Aloe ferox and stems Palmitic acid P. aeruginosa
quinones, tannins, coumarins, terpenes, lectins, and saponin,S.which aureus have been studied
due to their mechanisms of action against drug-resistant
Gallic acid pathogenic
E. coli bacteria [2,110,111].
Asparagus
These africanus
plants Roots
can be proactively Hydroxybenzoic
bactericidal acid
or bacteriostatic P. aeruginosa
because they have [97]less
Hydroxycinnamic acids A. baumannii
nitrogen, sulfur, phosphorus, and halogens, and exhibit overall enhanced scaffold variety,
E. faecalis
molecular complexity, stereochemical abundance, Luteolin diversityE.in coli the ring system, and
Leaves, roots, β-sitosterol
carbohydrate
Artemisia afra contents [112,113]. These features allow plant products to modify or inhibit
K. pneumoniae [98]
and stems Apigenin
protein interactions, thereby presenting Myo-inositol P. aeruginosa
themselves as effective modulators of immune
S. aureus
response, mitosis, apoptosis, and signal transduction [112,114]. In this way, the microbial
E. coli
cell can be affected inRoots,
Boscia albitrunca
several ways, including the inhibition
Anthraquinones, and disruption[69,99]
K. pneumoniae
of cell
leaves martynoside
membrane and cell wall functions and structures, interruptionS.of nucleic acid replication
aureus
and ATP synthesis, generation of reactive oxygenBetane
Stachdrine species, inhibition of the formation of
E. coli
biofilms, disruption ofRoots,
Capparis tomentosa
quorum sensing at all stages, andP. aeruginosa
Strychnine via synergy with[100] other
fruit 3-hydroxy-4methoxy-
antimicrobial agents [94,115–121]. K. pneumoniae
3-methyl-oxindole
E. coli
3.4.1. Antibacterial Activity
Cassia abbreviata Bark
of Plant-Derived Bioactive Compounds
Spectaline
K. pneumoniae [101]
Iso-6-cassine
P. aeruginosa are classified into
Medicinal plants associated with low molecular weight antibiotics
two types, phytoanticipins
Seeds, and phytoalexins [122]. Phytoanticipins
Labdane, isolabdane, E. coli are involved in
Colophospermum mopane husks, and clerodane S. aureus [102]
leaves diterpenoids Enterococcus
Bark,
Vitexin, saponaretin, E. coli
Combretum hereroense leaves, [103]
combretacin S. aureus
roots
Biomedicines 2023, 11, 2605 13 of 30
Table 3. Cont.
MDR Bacteria
Plant Part Active Compound Reference
Active Against
E. coli
1β,2β,3β-trihyddoxy-
K. aerogenes
Commiphora glandulosa Resin urs-12-ene-23-oic- [70]
P. aeruginosa
rhamnoside
S. aureus
S. aureus
Dichrostachys cinerea Roots Tanninic acid E. coli [57]
P. aeruginosa
Gemacrene, E. coli
Aerial parts of
Dicoma anomala Sond. β-farnasene, S. aureus [104]
the plant
α-humulene P. aeruginosa
Rhizomes, S. aureus
Elephantorhiza goetzei Tanninc acid [72]
roots P. aeruginosa
Bark, Diopyrin
E. coli
Euclea undulata leaves, Lupeol [62]
P. aeruginosa
roots 7-methyljuglone
Oleanolic acid S. aureus
Hibiscus calyphyllus Aerial parts [40]
β-amyrin P. aeruginosa
Camphor
Leaves, K. pneumoniae
Myrothamnus flabellifolius 1,8-cineole [105,106]
twigs S. aureus
α-pinene
Anacardic acid E. coli
Quercetin S. aureus
Ozoroa paniculosa Leaves [61]
Proanthocyanidin P. aeruginosa
Gallotannin E. faecalis
Bulbs, roots, E. coli
Haemanthamine
Scadoxus puniceus leaves, K. pneumoniae [107]
Metolachlor
stems S. aureus
Hydroxystilbene
glycoside, triterpene E. coli
Roots, stems,
Terminalia sericea sericoside, resveratrol- K. pneumoniae [64,66]
bark, leaves
3-O-β-D-rutinoside, P. aeruginosa
Lupeol, Anolignan B
Bark,
Catechin
fruit,
Ximenia Gallic acid E. coli
roots, [53,55]
americana/Ximenia caffra Quercetin P. aeruginosa
seeds,
Proanthocyanidin
leaves
3.4. Therapeutic Potential of Traditional Medicinal Plants against MDR Bacteria

Antibiotics are definitely the cornerstones of modern medicine; unfortunately, we
are still experiencing the rapid spread of foodborne pathogens, emergence of antibiotic-
resistant microbial strains, and increasing failure of available chemotherapeutics [108].
Hence, there is a need for efficient antibacterial agents to fill the gap for the discovery
and development of anti-MDR agents. Natural products dominate the preferred chemical
scaffolds for the discovery of antibacterial agents [13]. In fact, in Africa, traditional healers,
herbalists, and individuals have used a variety of wild leaves, roots, barks, fruits, and seeds
to combat miscellaneous bacterial illnesses and diseases [109]. Medicinal plants have a wide
array of phytochemicals, alkaloids, phenolics, polyphenols, flavonoids, quinones, tannins,
coumarins, terpenes, lectins, and saponin, which have been studied due to their mecha-
nisms of action against drug-resistant pathogenic bacteria [2,110,111]. These plants can be
proactively bactericidal or bacteriostatic because they have less nitrogen, sulfur, phosphorus,
and halogens, and exhibit overall enhanced scaffold variety, molecular complexity, stere-
ochemical abundance, diversity in the ring system, and carbohydrate contents [112,113].
These features allow plant products to modify or inhibit protein interactions, thereby pre-
senting themselves as effective modulators of immune response, mitosis, apoptosis, and
Biomedicines 2023, 11, 2605 14 of 30
signal transduction [112,114]. In this way, the microbial cell can be affected in several
ways, including the inhibition and disruption of cell membrane and cell wall functions and
structures, interruption of nucleic acid replication and ATP synthesis, generation of reactive
oxygen species, inhibition of the formation of biofilms, disruption of quorum sensing at all
stages, and via synergy with other antimicrobial agents [94,115–121].
Antibacterial Activity of Plant-Derived Bioactive Compounds

Medicinal plants associated with low molecular weight antibiotics are classified into
two types, phytoanticipins and phytoalexins [122]. Phytoanticipins are involved in micro-
bial inhibitory actions while phytoalexins are generally antioxidative and are synthesized
de novo by plants in response to microbial infections [122,123]. Many studies have shown
that the antimicrobial activity of the plant-derived active compounds, namely alkaloids,
phenylpropanoids, and terpenoids, have different capacities to promote cell wall dis-
ruption and lysis, induce reactive oxygen species production, inhibit biofilm formation,
inhibit cell wall construction, inhibit microbial DNA replication, inhibit energy synthesis,
inhibit bacterial toxins from effecting the hosts, and even prevent synergetic resistance
to antibiotics [120,124–128].
Inhibition and Disruption of Cell Wall Construction

The cell wall is the principal stress-bearing and shape-maintaining element in bacteria.
Cell walls can be broadly classified into two polyphyletic groups, Gram-positive and
Gram-negative, each arising from structural differences linked to the bacterial interactions
with the environment [129,130]. Gram-negative cell walls have an additional membrane
covered in lipopolysaccharides, while Gram-positive walls contain only one membrane and
have a thicker layer of peptidoglycan containing negatively charged teichoic acids [129].
The biosynthesis of bacterial cell wall peptidoglycan, also called murein, is a complex
process that involves enzyme reactions that take place in the cytoplasm on the inner side
and outer side of the cytoplasmic membrane [130,131]. Teichoic acid is synthesized as a
lipid-linked precursor in the cytoplasm, translocated across the cytoplasmic membrane,
and then covalently bonded to the peptidoglycan by the involvement of specific enzymes,
namely TagF, TagG, and TagH [130,132]. Since the bacterial cell wall is responsible for
many metabolic activities, both directly and indirectly, the integrity of the membrane
is of paramount importance, and its disruption can lead to metabolic dysfunctions and
ultimately bacterial lysis [129,130,132]
Phenolic compounds and quinones, which are aromatic compounds, are usually
targeted to microbial cell surface adhesins and membrane-bound polypeptides, which may
disrupt the development of the cell wall and lead to eventual cell lysis [116]. Catechins
attract lipid bilayers of the membrane; they form hydrogen bonds, which attract polar
head groups of lipids at the membrane edge, which causes structural changes in the cell
membrane [133]. Phenolic compounds consist of a hydroxyl functional group, which leads
to reactions of hydroxylation, while flavonoids, in particular, are able to complex with
bacterial cell walls and disrupt microbial membranes [116,117]. Flavonoids, quercetin,
rutin, naringenin, sophoraflavanone, chalcone, and tiliroside are linked to decreased lipid
bilayer thickness and fluidity levels and increased membrane permeability and eventual
leakage of intracellular proteins and ions in S. aureus and S. mutans [11,134]. Other active
flavonoids, including acacetin, apigenin, morin, and rhamnetin, are known to cause the
disarrangement and disorientation of the lipid bilayer, thereby weakening the bacterial cell
wall and ultimately causing vesicle leakage [125,135]. Flavonoids such as EGCG, penta-
hydroxy-flavones, and dimethoxyflavones inhibit the malonyl CoA-acyl carrier protein
transacylase, which regulates bacterial fatty acid synthase-II [136,137].
Inhibition of Bacterial DNA Replication and ATP Synthesis

Plant-derived bioactive compounds have been proven to halt many enzymes that are
linked, directly and indirectly, to DNA replication, transcription, and translation [138].
Biomedicines 2023, 11, 2605 15 of 30
The replication of DNA is an ATP-dependent process, and the initiation of DNA

replication thereof is linked to the growth-dependent accumulation of the ATP-bound form
of the highly conserved protein DnaA [139]. As the bacterial cell grows and develops
until it reaches a specified mass or size, DnaA-ATP accumulates. Adenosines, ATPase,
and DnaA initiate DNA replication by mediating the unwinding of an ATP-rich stretch
of DNA within the origin, facilitating the addition of the replication machinery [139].
Flavonoids such as baicalein, morin, quercetin, and silymarin can constrain the function
of ATPases, which is the hydrolysis of a phosphate bond in ATP to generate energy,
and can obstruct ATP synthesis [119,140]. This obstruction of the synthesis of ATP can
disrupt the unwinding of DNA and halt DNA replication. Additionally, EGCG, flavones,
and proanthocyanidins have been implicated in the inhibition of the enzymatic activity of
ATPase in some bacteria [136,141]. Apigenin, genistein, and myricetin have been recognized
as DNA gyrase inhibitors [138,142]. They have been proven to intercalate with the stacking
of nucleic acid bases, as well as binding to the β subunit of gyrase and the corresponding
blockage of the ATP binding pocket to halt DNA and RNA [122,143]. Helicase is responsible
for unzipping the DNA double strand during the early stages of DNA replication [144].
Luteolin, morin, and myricetin have been demonstrated to inhibit the DNA-separating and
-rearranging capacity of the helicases of E. coli [145,146].
Berberine and harmane, which are alkaloids, have been reported to intercalate with
bacterial DNA and lead to the impairment of the cell membrane, consequently leading
to cell death [147]. In another study, E. coli and L. monocytogenes were treated with trans
cinnamaldehyde, an essential oil produced by cinnamon, and it was found that it can
downregulate F1F0-ATPase, resulting in rapid reductions in ATP, thereby preventing the
concentration of cellular ATP and reducing the growth of the bacterial cell [148]. According
to Almuhayawi (2020) [149], the ATPase activity in E. coli was also inhibited as a result of
quercetin binding to the bacterial DNA gyrase B subunit. The disruption of ATP synthesis
and DNA replication in bacterial cells can lead to growth disturbances, a compromised
cellular structure, and reduced resistance against conditions that may cause cell destruction
and ultimate lysis [148,149].
Disruption of Pathogenicity Activities

The pathophysiology of a microbial infection in a host is mediated by multiple viru-
lence factors, which are expressed at different stages of infection to cause the disease. These
factors include capsule production, toxin production, and hydrolytic protein production;
hence, virulence factors are the prime targets for therapeutic interventions and vaccine de-
velopment [150]. Microbial toxins include exotoxins (secreted by bacteria) and endotoxins
(released after bacterial lysis). Many phenolic compounds can affect enterotoxin production
through several modes of action, including translation or transcription inhibition, the dis-
ruption of secretory mechanisms, the inhibition of quorum sensing regulatory systems, and
toxin inactivation or neutralization [150–152]. RG tannin and apple phenols were reported
to inhibit ADP–ribosyltranferase activity that is critical for cholera toxin action, leading to
reductions in toxin-induced accumulation in mouse ileal loops [153,154]. Toxin-mediated
pathogenesis is more aggressive because even post cell lysis the toxin remains behind and
continues virulence [155]. Therefore, compounds that do not only cause cell death but
also inactivate toxins are more effective against this kind of virulence. Phenolic hydroxylic
compounds can inactivate or neutralize bacterial exo-proteins by forming hydrogen bonds
with active sites of enzymes or toxins to inhibit their activity [151,156]. In some studies,
resveratrol disrupted the toxin’s internalization and activity, epigallocatechin gallate and
procyanidin blocked the toxin binding and occupied the binding sites, and kaempferol and
quercitrin could directly inhibit the activity of the catalytic subunit [156,157]. Gallotannins
have inhibitory effects on microorganisms. These effects are attributed to their complex-
ing properties and ability to interact with proteins and inhibit enzyme activity via their
chelation of the metal ions of the active sites [158].
Biomedicines 2023, 11, 2605 16 of 30
Generation of Reactive Oxygen Species

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) can be formed from
the partial reduction of molecular oxygen and nitrogen through many continuous metabolic
pathways, involving both enzyme-catalyzed and non-enzymatic reactions [159–161]. ROS
can attack diverse targets to exert antimicrobial activity, which helps to account for their
versatility in mediating host defense against a vast range of disease-causing pathogenic
organisms [160,161]. In fact, it is the host’s NADPH-dependent NOX2 phagocyte oxidase
complex in the immune system that is responsible for the generation of ROS [160]. Therefore,
many phenols that have the capacity to dabble between pro-oxidant and antioxidant
activities because of their hydroxyl groups can be easily coupled with the human’s defense
systems against pathogens [162,163]. Examples of these include quercetin and rutin; with
their hydroxyl groups they carry out hydroxylation with the lipid bilayer of the bacteria
and prevent the generation of ROS [11,116,117]. Upon penetrating the inner cell membrane,
phenols can be oxidized by ROS, converting them into pro-oxidants, which are able to
oxidize lipids, proteins, and DNA, leading to bacterial cell lysis [163].
ROS readily attack the polyunsaturated fatty acids of the fatty acid membrane to
initiate lipid peroxidation, which compromises the integrity of the cell membrane and
facilitates eventual cell lysis [164]. Some ROS include superoxide, hydrogen peroxide,
hydroxyl radical, alkoxyl radicals, and singlet oxygen. They have different kinetics and
levels of activity [162]. Hydrogen peroxide is a covalent and uncharged molecule that
readily mixes with water, and is treated as such by cells, meaning it diffuses across the
cell membrane with ease [161]. It can also form redox reactions and highly reactive free
radicals, which may be aggressively oxidative and can impair the functions of many
metabolic processes [161].
In this manner, plant-derived compounds with hydroxyl tails or double bonds can
be oxidized to become phenoxyl radicals or quinone intermediates, meaning they be-
have as pro-oxidant systems [120,164]. In the presence of transition metals, they can
fragment DNA and lead to mutation and cell death [165]. Catechins, for instance, enhance
the production of oxidative stress as ROS and RNS [166]. In this way, they can cause
altered membrane permeability, bond to the highly negatively charged lipids and lipo-
somes, and facilitate cell damage and eventually death [167]. They are also linked to the
leakage of intracellular proteins and ions, as they also disturb the membrane transport
system [164,166,167]. Epigallocatechin gallate, in high concentrations, exerts its mode of
action of killing bacteria via the generation of ROS, causing alterations of the membrane
permeability and membrane damage [120].
Formation of Biofilms Inhibition

Biofilm formation is a process whereby microorganisms irreversibly attach to and
grow on a surface and produce extracellular polymers that facilitate attachment and matrix
formation, resulting in alterations of the phenotype of the organisms with respect to the
growth rate and gene transcription [168]. These surfaces of attachment may take many
forms, including the surface of the host that is colonized and infected [168,169]. The
presence of mobility structures such as flagella, fimbriae, and pili is most important for
microbial attachment [168,169]. Microbial cells, via these appendages, temporarily attach
to the surface, as they prepare to form colonies and exude extracellular polymers that will
then attach permanently to the surface [170,171].
Flavonoids have been described to cause the aggregation of multicellular composites
of bacteria and cause psuedobacterial growth after aggregation, which indicates that
flavonoids are potent antibiofilm compounds [122]. Flavonoids such isovitexin, galangin,
EGCG, trihydroxyflavanols, and 3-O-octanoyl-epicatechin have been shown to inhibit
the multicellular aggregation of pathogenic bacteria [122,124,127,172]. Moreover, chrysin,
phloretin, naringenin, epicatechin gallate, and proanthocyanidins have been proven to
inhibit N-acyl homoserine lactone-mediated quorum sensing [173–175]. The synthetic
flavonoid lipophilic-3-arylidene was found to be very active against S. aureus, S. epidermidis,
Biomedicines 2023, 11, 2605 17 of 30
and E. faecalis due to a bacterial cell clump that influences the integrity of the cell wall as a
result of biofilm disruption [155]. Phloretin was also proven to prevent the formation of
fimbriae in E. coli by reducing the expression of the curli genes (csgA, csgB) and toxin genes
(hemolysin E, Shiga toxin), eventually halting the formation of the biofilm [176,177].
In one study, the components of cranberry juice were hypothesized to interact with
hydrophobic proteins on the surface of the bacterial cell [178]. Streptococcus mutans and
Streptococcus sobrinus were treated with cranberry juice, and it was found that the cranberry
juice reduced the surface hydrophobicity of the cells, interfering with adhesion and the
initial stages of biofilm formation. Since hydrophobicity is an important factor in the initial
attachment of the bacteria to a surface, reducing the hydrophobicity decreases the likelihood
of adhesion [179]. Therefore, preventing biofilm formation is a potential method of curbing
bacterial colonization and eventual pathogenicity, possibly through the engagement of
plant-derived bioactive compounds.
Quorum Sensing (QS) Inhibition

The discovery of bacterial communication systems (QSsystems) that orchestrate im-
portant temporal events during the infection process has afforded a novel opportunity to
ameliorate bacterial infections using compounds and possibly overriding bacterial signal-
ing mechanisms [180]. Many plant species produce secondary metabolites and compounds
that can control the growth of microbes and have traditionally been used to treat human
microbial infections via anti-quorum sensing. The therapeutic substances in Centella asiatica L.
Urban are saponin-containing triterpene acids and their sugar esters, e.g., Asiatic acid,
madecassic acid, and asiaticosides, which have been shown to treat skin problems and
heal wounds [181,182]. In fact, in a study by [183], the anti-quorum sensing potential
of C. asiatica was investigated using Chromobacterium violaceum and P. aeruginosa PA01.
The anti-quorum sensing activity of an ethanolic extract and ethyl acetate fraction of the
herb were investigated against C. violaceum. The ethanol extract showed quorum sensing
inhibition against violacein production, while the ethyl acetate fraction was four times
more active against violacein production, without significantly affecting the growth [183].
The ethyl acetate fraction also inhibited quorum-sensing-regulated phenotypes, pyocyanin
production, elastolytic and proteolytic activities, swarming motility, and biofilm formation
in P. aeruginosa PA01 in a concentration-dependent manner [183].
Bacteria are consistently subjected to environmental stimuli such as nutrient avail-
ability, temperature, and pH changes. They in turn have developed multiple systems that
form cell-to-cell communication via the use of autoinducers of N-acyl-homoserine lactone
(AHLs) for Gram-negative bacteria and oligopeptides for Gram-positive bacteria in order
to activate specific gene expression and QS systems [184–186]. The AHL-mediated QS
function requires three major components: an AHL signal molecule, an AHL synthase
protein to make the AHL signal (LuxI), and a regulatory protein that responds to the
surrounding concentration of AHL [187,188]. At high AHL concentrations, the sigma
receptor protein (LuxR) forms a complex with AHL and becomes activated; this activa-
tion triggers the expression of genes that are linked to biofilm formation and virulence
during pathogenesis [185,187].
The traditional treatment of bacterial infections is anchored on compounds that ei-
ther kill or inhibit bacterial growth [189]. With the development of resistance against
and tolerance for these antibacterial agents, hacking into the quorum sensing systems
using plant-derived substances may pose a potential novel opportunity to amend bacterial
virulence [190,191]. This is because many compounds that have been proven to override
bacterial signaling are present in medicinal plants, and bacterial communication systems
are responsible for the orchestration of the important progressive events during the in-
fection process [186,188,190,191]. Therefore, the strategies aiming to interrupt bacterial
quorum sensing circuits possibly include the inhibition of AHL or oligopeptide signal
generation, inhibition of AHL or oligopeptide signal distribution by antagonization or
degradation, and prevention of AHL signal reception via competitive and non-competitive
Biomedicines 2023, 11, 2605 18 of 30
inhibition [184,190]. The plant-derived molecules that affect these AHL-mediated quorum
sensing stages include sulfur-containing compounds, monoterpenes, monoterpenoids,
phenylpropanoids, benzoic acid derivatives, diarylheptanoids, coumarins, flavonoids,
and tannins [189,192].
Inhibition of AHL or Oligopeptide Signal Generation

The AHL signal is synthesized at a low basal level by the AHL synthase. Often the
quorum sensor is subject to autoinduction because the gene encoding the signal synthase
is among the target genes; hence, a positive feedback regulatory loop is created [189,192].
The autoinduction allows a rapid increase in signal production and dissemination,
which in turn induces a quorum-sensing-controlled phenotype throughout the bacterial
population [189]. AI-1 is an AHL that is involved in intraspecies communication,
whereas AI-2, a furanosyl borate diester, has been suggested to play an important role
in interspecies communication [193]. Genome sequencing revealed the presence of luxS
homologs (encoding the AI-2 signal synthase) in many pathogens, including E. coli,
Helibacter, Neisseria, ZPorphyromonas, Proteus, Salmonella, E. faecalis, S. pyogenes, and S. aureus,
and in some of the pathogens luxS is required for virulence [194,195]. The luxS gene
responsible for the production of AI-2 is produced from S-ribosylhomocysteine, a prod-
uct in S-adenosylmethione utilization [194,196]. LuxS cleaves S-ribosylhomocysteine
to form homocysteine and 4,5-dihydroxy-2,3-pentanedione, which is subsequently con-
verted to AI-2 through an unknown biochemical pathway [193,197]. LasI, which is part
of one of the quorum sensing systems in P. aeruginosa (LasR/I and RhII/R), is essen-
tial for the production of the AHL molecule, N-(3oxododecanoyl)-L-homoserine lactone
(3O-C12-HSL), and lasR is the transcriptional regulator [118,198]. The second QS system
comprises the RhII and RhIR proteins [118,198]. The RhII synthase mediates the syn-
thesis of the signal molecule, N-butyryl-homoserine lactone C4-HSL, while RhIR is the
transcriptional regulator [198,199].
The majority of bacteria that produce AHL signals encode one or more genes homol-
ogous to luxI of Vibrio fischeri [189]. The expression of these genes in a heterologous host
background has demonstrated that the LuxI-type protein is required and sufficient for
the production of AHL signals. Additionally, the catalysis of AHL synthesis involves a
sequentially ordered reaction mechanism that uses S-adenosyl methionine (SAM) as the
amino donor for the generation of the homoserine lactone ring moiety and an appropriately
charged acyl carrier protein (ACP) as the precursor for the acyl side chain of the AHL
signal [200]. Various analogs of SAM, such as S-adenosylcysteine and sinefungin, have
been demonstrated to be potent inhibitors of AHL synthesis catalyzed by the P. aeruginosa
RhII protein [189]. Moreover, such inhibition can be due to interference with acyl homes-
rine lactone production (luxI effect) or a transcription response (luxR effect) [191]. Protein
inhibition at the ribosomal level can be a means of hacking into the quorum sensing system
of the pathogen.
Trans-cinnamaldehyde was reported to reduce the expression of luxR, which codes for
the transcriptional regulator of quorum sensing in C. sakazakii [201]. Similarly, garlic extract
and p-coumaric acid inhibited quorum sensing in quorum sensing strains, indicating
that plant compounds potentially modulate virulence by affecting quorum sensing in
microbes [150]. In one study, S. aromaticum exhibited high quorum sensing inhibition ability
and concentration-dependent violacein pigment inhibition of C. violaceum, which is also
correlated with biofilm formation inhibition [202,203]. The inhibition of biofilm formation
indicated that EPS was not formed and that the bacteria were unable to attach to the host
for the formation of biofilms [204].
Decreasing the active signal molecule concentration in the environment can inhibit
bacterial cell-to-cell communication. The reversible hydrolysis of AHLs at high pH levels
has been recorded in some instances and was linked purely to alkaline conditions [205]. In
other cases, the degradation of the AHLs was linked to enzymatic activity. Bacillus species
produce an enzyme, termed AiiA, which catalyzes the hydrolysis of AHL molecules. The
Biomedicines 2023, 11, 2605 19 of 30
expression of this gene in the plant pathogen Erwinia carotovora resulted in the reduced
release of AHL signals, decreased extracellular pectolytic enzyme activity, and attenuated
soft rot disease symptoms in all plants tested [206]. Moreover, transgenic plants expressing
AiiA have been shown to be significantly less susceptible to infection by E. carotovora [168].
Therefore, AHL-degrading or antagonizing proteins are of great clinical potential for use in
the prevention of diseases caused by quorum-sensing-proficient bacterial populations.
Blocking of the quorum sensing signal transduction can be achieved by an antagonist
molecule capable of competing or interfering with the native AHL signal for binding to the
LuxR-type receptor [180,192]. Competitive inhibitors share structural similarities with the
native AHL signal; in that way they bind and occupy the AHL binding site and block the
LuxR-type receptor [180,189,207]. The non-competitive inhibitors, on the other hand, show
no or little structural similarities to AHL signals, as these molecules bind to different sites
on the receptor protein. In this manner, it would be more effective to locate competitive
inhibitors. AHLs have acyl side chains, whose length and flexibility are also crucial in the
effective binding of the AHL to the LuxR-type receptor [188,208]. Receptors also have ion
ends that are respective to their partners when coupling.
Several plants secrete bioactive compounds that mimic bacterial AHL signal activ-
ities and affect quorum-sensing-regulated behaviors in associated pathogens [209,210].
Quercetin, among other phenols, was implicated to bind the LuxR-type receptor pro-
teins (LasR, RhIR, and CviR) and inhibit quorum-sensing-regulated bioluminescence
in V. harveyi [211]. The Australian red macroalga D. pulchra, Hoslundia opposita, and
Lippia javanica produce ranges of furanone compounds that display antifouling and an-
timicrobial properties [212,213]. Furanones were implicated in the displacement of ra-
diolabeled AHL molecules from LuxR, suggesting competitive inhibition by binding on
the LuxR receptor site [180,207]. Moreover, these furanones have been linked to the in-
hibition of AHL-controlled virulence factor production and pathogenesis in P aeruginosa.
The furanones are also linked to the inhibition of the quorum-sensing-controlled lumi-
nescence and virulence of the black tiger prawn pathogen Vibrio harveyi, as well as the
inhibition of the quorum-sensing-controlled virulence of E. carotovora [189,192,207,214].
Anti-quorum-sensing activity against S. aureus was also linked to L. javanica-derived
limonene, carvone, geranial, and neral essential oils [189,192,207,209,214]. Other flavonoids
such as apigenin, kaempferol, naringenin, and quercetin were also proven to possess
anti-quorum-sensing capacities by inhibiting enteroaggregative biofilm formation in a
concentration-dependent manner [215,216].
Synergy with Other Antimicrobial Agents

The synergistic behavior of traditional antibiotics with compounds obtained from
plants offers many advantages, such as increased efficiency, decreased undesirable effects,
increased stability or bioavailability of free agents, and the ability to obtain suitable thera-
peutic effects at lower doses [217]. Many studies have demonstrated that the synergism
between different antibacterial agents can yield better effects than merely one. This can in-
clude the combined effects of plant-derived compounds alone or plant-derived compounds
with antibiotics. Mixing plant extracts with different commercial antibiotics enhanced and
synergized their antibacterial effects [218]. Additionally, the synergic effects between dif-
ferent single compounds could trigger the antimicrobial effectiveness of the plant-derived
compounds and may reduce the resistance of many pathogenic microorganisms.
In one study, anti-bacterial activity against Listeria monocytogenes biofilm was more
effective where the synergism between a-pinene, limonene, and linalool was at play than
when each single component was used [219]. Carvacrol (Table 1), γ-terpinene, and
ρ-cymene can be effective and have synergistic effects when combined; this is due
to the action of ρ-cymene, which works as a mediator for the transportation of car-
vacrol and γ-terpinene across the cell walls and cytoplasmic membranes of pathogenic
microorganisms [220]. In another study, plant extracts from Mezoneuron benthamianum,
Securinega virosa, and Microglossa pyrifolia increased the susceptibility of major drug-resistant
Biomedicines 2023, 11, 2605 20 of 30
bacteria such as S. aureus and P. aeruginosa to antibiotic norfloxacin [221]. Similarly, geran-
iol, extracted from Helichrysum italicum, was found to restore the efficacy of quinolones,
chloramphenicol, and β-lactams against multi-drug-resistant pathogens, including
Acinetobacter baumannii [222]. The flavonoid chalcone can also be used as a therapeutic agent
against infections of methicillin-resistant S. aureus strains [223]. A bioactive macrocyclic
spermine alkaloid from Albizia schimperiana was linked to the inhibitory activity against
methicillin-resistant S. aureus and E. coli [224].
Essential oils from different plants demonstrated activities against the emerging multi-
drug-resistant bacteria in human skin; this could be used to combat the problem of untreat-
able skin diseases. In a study by Haroun and Al-Kayali [225], T. spicata extracts showed
the ability to increase the susceptibility of multi-drug-resistant strains of S. aureus and
K. pneumoniae to various antibiotics. Essential oils and organic extracts of A. afra, A. betulina,
and S. frutescens, in combination with ciprofloxacin, also displayed synergistic interactions
against E. coli [225]. Arasu et al. evaluated the antibacterial activities of essential oils
of Sesamum indicum, Allium sativum, and Acorus calamus; they found out that essential
oils alone and in combination with antibiotics had high activity levels against some food
spoilage bacteria [226]. Indeed, medicinal plants, unlike pharmacological drugs, com-
monly have several chemicals working together catalytically and synergically to produce a
combined effect that surpasses the total activity of the individual constituents [227]. The
combined effect of these substances tends to increase the activity of the main medicinal
constituents by speeding up or slowing down their assimilation in the body. In one study,
plant extracts from Mezoneuron benthamianum, Securinega virosa, and Microglossa pyrifolia
increased the susceptibility of major drug-resistant bacteria such as S. aureus and
P. aeruginosa to antibiotic norfloxacin [221]. Similarly, geraniol, extracted from Helichrysum
italicum, was found to restore the efficacy of quinolones, chloramphenicol, and β-lactams
against multi-drug-resistant pathogens, including Acinetobacter baumannii [222].
4. Conclusions and Future Research

Novel therapeutic options are crucial in combatting AMR and reducing the burden of
infectious diseases. Bioactive compounds from indigenous medicinal plants alone or in
combination with existing antimicrobials offer promising solutions towards overcoming
global AMR threats. As already shown in this review, the African continent is rich in diverse
medicinal plant species, and the current research should focus on new discoveries of plant
secondary metabolites with antimicrobial properties. There have already been advances
in the development of new antimicrobial therapies, which are currently supported by
technological advancements in “omics” techniques such as proteomics and metabolomics.
Microbial genomics has contributed globally to the understanding of bacterial resistance
mechanisms, evolution, and dissemination, allowing better treatment response, prevention,
and control strategies. However, Africa is still lagging behind in “omics” research due
to socioeconomic factors a lack of access to and sustainable use of genomic sequencing
technologies. The economic challenges, limited infrastructure for “omics“ research, and
shortage of well-trained staff in the African continent have evidently been the downfall of
efforts towards combating AMR and the development of new antimicrobial drugs. Despite
these challenges, there is promising research in some parts of Africa, such as Botswana,
aimed at addressing AMR problems using secondary metabolites derived from medicinal
plants. The preliminary results from some of the indigenous plant extracts studied in
Botswana revealed great potential when tested against MDR bacteria. Therefore, extensive
research in this area of antimicrobial discovery remains critical towards combating AMR in
Africa and globally.
Supplementary Materials: The following supporting information can be downloaded at: https://
www.mdpi.com/article/10.3390/biomedicines11102605/s1. Table S1: Additional informations about
Biomedicines 2023, 11, 2605 21 of 30
Author Contributions: Conceptualization, A.M. and T.O.R.; validation, A.M., T.O.R. and G.R.; formal
analysis and investigation, B.N.M. and K.P.P.M.; writing—original draft preparation, T.O.R. and
A.M.; writing—review and editing, T.O.R., A.M., B.N.M. and K.P.P.M.; supervision, A.M. and G.R.;
project administration, T.O.R. and A.M. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Acknowledgments: We acknowledge the Department of Biological Sciences and Biotechnology and
Botswana International University of Science and Technology. Additionally, we would like to thank
and acknowledge Kathleen Hefferon for proofreading this manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
AMR Antimicrobial resistance

MDR Multi-drug-resistant
VRE Vancomycin-resistant Enterococci
CRAB Carbapenem-resistant Acinetobacter baumannii
CRE Carbapenem-resistant Enterobacteriales
ESBL Extended-spectrum β-lactamase
MRSA Methicillin-resistant Staphylococcus aureus
XDR Extensively drug-resistant
WHO World Health Organization
ECDC European Centre for Disease Prevention and Control
CDC Centres for Disease Prevention and Control
LMICs Low- and middle-income countries
ESKAPEE E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, Enterobacter species,
and E. coli
SCCmec Staphylococcal cassette chromosome mec
EGCG Epigallocatechin gallate
PBP2a Modified penicillin-binding protein
ROS Reactive oxygen species
RNS Reactive nitrogen species
AHL Autoinducers of N-acyl-homoserine lactone
QS Quorum sensing
SAM S-adenosyl methionine
ACP Acyl carrier protein
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biomedicines

Abstract: Antimicrobial resistance is considered a “One-Health” problem, impacting humans, ani-

Academic Editors: Israa M.S.

Received: 30 May 2023

Biomedicines 2023, 11, 2605. https://doi.org/10.3390/biomedicines11102605 https://www.mdpi.com/journal/biomedicines

2. Materials and Methods

Biomedicines 2023, 11, 2605 3 of 30

and bacteremia, especially in immunocompromised individuals [21]. P. aeruginosa displays

Table 1. Mechanisms of antibiotic resistance to common classes of antibiotics using healthcare.

Bacterial Strain Antibiotics Mechanism of Resistance Reference

Bacterial Strain Antibiotics Mechanism of Resistance Reference

H. procumbens of the sesame seed or Pedaliaceae family, popularly known as devil’s

Setswana Name Manner of Distribution in

Setswana Name Manner of Distribution in

Setswana Name Manner of Distribution in

Setswana Name Manner of Distribution in

3.3. Plant Secondary Metabolites with Antimicrobial Potential

Figure 2. ExamplesFigure 2. Examples of plant-associated

3.4. Therapeutic Potential of Traditional Medicinal Plants against MDR Bacteria

Antibacterial Activity of Plant-Derived Bioactive Compounds

Inhibition and Disruption of Cell Wall Construction

Inhibition of Bacterial DNA Replication and ATP Synthesis

The replication of DNA is an ATP-dependent process, and the initiation of DNA

Disruption of Pathogenicity Activities

Generation of Reactive Oxygen Species

Formation of Biofilms Inhibition

Quorum Sensing (QS) Inhibition

Inhibition of AHL or Oligopeptide Signal Generation

Synergy with Other Antimicrobial Agents

4. Conclusions and Future Research

AMR Antimicrobial resistance

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