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    Topic review

    African Antivirulence Plants

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    Antivirulence is the concept of blocking virulence factors produced by pathogenic organism. In regards to bacteria, the idea is to design agents that block virulence rather than kill bacteria population that generate more selective pressure leading to antibiotic resistance. African plants, through their huge biodiversity, present a considerable reservoir of secondary metabolites with a very broad spectrum of biological activities, a potential source of natural products targeting such non-microbicidal mechanisms. 

    1. Introduction

    Antimicrobial resistance, increasingly observed within a wide range of pathogenic bacteria, has become a worldwide threat to public health [1][2]. Over time, bacteria adapt to the drugs that are designed to kill them, evolving or selecting resistance mechanisms to ensure survival. The resistance of bacteria to antibiotics is a naturally occurring phenomenon, supposedly progressive over contact with antibiotics. However, the misuse and abuse of antibiotics led to a strong and rapid selective pressure, leading to an uncontrolled widespread development of antibiotic-resistant bacteria [3][4]. Beyond resistance to antibiotics, the ability of bacteria to develop effective biofilms represents one of the major obstacles in the fight against bacterial infections. Indeed, while planktonic lifestyle allows bacteria to easily diffuse in diverse environments, their biofilm lifestyle allows efficient colonization of biotic and abiotic surfaces and protection from environmental aggression [5].

    Undoubtedly, whenever new antimicrobial compounds would be discovered, their use will result in selective pressures, probably leading targeted bacteria to develop a resistance to these agents. This likely outcome stirs researchers to consider other strategies, notably based on the search for original compounds that impair virulence expression mechanisms and/or biofilm formation without affecting bacterial viability [6][7]. Striking such targets will likely impact invasion capabilities and aggressiveness of bacteria, as well as their ability to build protective barriers against host immune defenses or antibiotics; all the while, selective pressure would be minimized [8], most probably preventing or slowing down the apparition and spread of resistances.

    The expression of bacterial virulence factors is generally coordinated by quorum sensing (QS) mechanisms, a cell-to-cell communication system that allows bacteria to detect their population density by producing and perceiving diffusible signal molecules that synchronize common behaviors [6]. Depending on bacteria species, QS regulates the production of virulence factors, motilities, and/or biofilm formation. Thus, the disruption of QS signaling, also termed quorum quenching (QQ), appears as interesting adjuvant strategies in the fight against bacterial infections [9].

    Over millions of years of co-evolution, plants accumulated highly diverse secondary metabolites (so-called ‘natural products’), developing means of surviving in hostile environments that combine herbivorous insects and pathogenic bacteria, fungi, and viruses [10]. Given the huge diversity of flora and ecosystems in the world, the plants likely represent significant sources of innovative compounds with antivirulence properties. Indeed, several studies have already reported natural compounds, mainly isolated from plants, and synthetic compounds interfering with bacterial virulence [5][11]. For instance, ajoene, an allyl sulfide isolated from garlic (Allium sativum L., Liliaceae) and baicalin, a flavone glycoside isolated from Huangqin (Scutellaria baicalensis Georgi, Lamiaceae) have been reported to inhibit both virulence factors production and biofilm formation in P. aeruginosa through QQ pathways [12][13].

    From an estimated African biodiversity of ~45,000 plant species, only 5000 have documented medicinal use [14]. The list of drugs provided by the African flora appears quite short (less than 100 active compounds) [15] compared with those from other traditional medical systems such as Traditional Chinese Medicine (more than 2000 active compounds from Chinese herbal) [16], suggesting an unrivalled opportunity for the discovery of new drugs.

    2. African Plant Extracts with Antivirulence Activities

    2.1. Activities on Gram-Negative Bacteria

    Various South African medicinal plants have been widely investigated for their antivirulence activities against various Gram-negative bacteria:

    (i) The hexanic extract from South African Kigelia africana (Lam.) Benth. (Fruits, Bignoniaceae) used to treat dysentery, reduces the production of violacein in C. violaceum ATCC 12472 by 65% when tested at 660 µg/mL [17]. Additionally, this extract interferes with the QS mechanism in A. tumefaciens by affecting the luxI synthase gene and the LuxR transcriptional regulator of autoinducers;

    (ii) South African plants, used to treat urinary tract infections, have been studied by Baloyi et al. [18] for their effects on the production of violacein in C. violaceum ATCC 12472. At a final concentration of 330 µg/mL, the extracts of Cenchrus ciliaris L. (bark; methanol; Poaceae), Cryptocarya latifolia Sond. (bark; methanol; Lauraceae), Eucomis autumnalis (Mill.) Chitt. (bulb; methanol; Aspaagaceae), Hydnora africana Thumb. (bark; methanol; Aristolochiaceae), Hypoxis hemerocallidea Fisch., C.A.Mey. & Avé-Lall. (corme; dichlorométhane; Hypoxidaceae), Rhoicissus tridentata (L.f.) Wild & R.B. Drumm (root; methanol; Vitaceae), Baccharoides adoensis (Sch.Bip. ex Walp.) H.Rob. (synonym of Vernonia adoensis Sch.Bip. ex Walp.) (bark; aqueous; Asteraceae), Bauhinia bowkeri Harv. (root; aqueous; Fabaceae) inhibit the production of violacein in C. violaceum ATCC 12472 (from 4 to 43% inhibition);

    (iii) Plants from the Myrtaceae family, endemic to South Africa and traditionally used to treat different ailments such as diarrhea, diabetes, reproductive problems, and respiratory diseases, have been investigated for their antibiofilm activity against various Gram-negative bacteria, including P. aeruginosa ATCC 27853, Salmonella ser. typhimurium ATCC 39183, and E. coli ATCC 25922 [19]. It has been highlighted that acetone extracts of leaves from different Syzygium and Eugenia species, particularly S. legatii Burtt Davy & Greenway and E. erythrophylla Strey, at 1000 µg/mL reduce biofilm formation (from 59–100% inhibition) but were unable to destroy pre-formed biofilms. These extracts exert in planktonic growth condition, a Minimal Inhibitory Concentration (MIC) values ranging from 40 to 310 µg/mL and relatively low cytotoxicity towards kidney epithelial cells (Vero) as concentrations of 140 to 1140 µg/mL inhibit cell viability by 50% (LC50); this indicates potentially safe herbal products;

    (iv) The ethanolic extract of the leaves of Lessertia frutescences (L.) Goldblatt & J.C.Manning (synonym of Sutherlandia frutescens (L) R.Br.) (Fabaceae), showed antibiofilm activity (90% inhibition) in P. aeruginosa ATCC 35032 and inhibition (>80%) of pyocyanin and LasB elastase [20].

    Finally, (v) the methanolic extract of the South African plant Sclerocarya birrea (A.Rich.) Hoch. (trunk bark; Anacardiaceae) has been proposed to exhibit anti-QS activity as it inhibits the production of pyoverdine, protease and motility as well as biofilm formation (78% inhibition) in P. aeruginosa MTCC 2453 at the concentration of 100 µg/mL [21].

    Plants from Western Africa, and particularly seven medicinal plants from Burkina Faso, have been also investigated for their impact on C. violaceum and P. aeruginosa QS mechanism and on P. aeruginosa biofilm formation; antivirulence activities of these Burkinabe plants are summarized in Table 1.

    Table 1. Antivirulence activities of Burkinabe medicinal plants against Gram-negative bacteria.

    These include Acacia dudgeoni Craib. ex Holl (Mimosaceae), used in the treatment of diarrhea and childhood dysentery [22][27]; Balanites aegyptiaca (L.) Delille (Zygophyllaceae) [23], traditionally used for the treatment of respiratory tract diseases, skin diseases, and wounds; Crossopteryx febrifuga (Afzel ex G. Don) Benth. (Rubiaceae) used in the treatment of various infectious diseases such as typhoid fever, respiratory infections, infected wounds, and dental diseases [24]; Terminalia leiocarpa (DC.) Baill. (synonym of Anogeissus leiocarpus (DC) Guill. et Perr.) (Combretaceae), also used to treat respiratory diseases and wounds [25]; Terminalia macroptera Guill. & Perr. (Combretaceae) [23], traditionally used for the treatment of respiratory tract diseases, skin diseases and wounds; Vachellia seyal (Delile) P.J.H.Hurter (synonym of Acacia seyal Delile) Del (Fabaceae) [26] traditionally used to treat toothache, dysentery, and burns [28] with reported potent antimicrobial activity [29]; and Zanthoxylum zanthoxyloides (Lam) Zepern. and Timler (Rutaceae) also used to treat typhoid fever, respiratory infections, infected wounds, and dental diseases [24].

    Plants from Eastern Africa have been also investigated for their QQ properties in a E. coli model. About 25 medicinal plant extracts (roots, bark, and leaves; ethanol 50% v/v) used in southwestern Kenya to treat gastrointestinal and urinary tract infections were tested against a transformed E. coli Top 10 reporter QS strain that expresses green fluorescent protein (GFP) when induced by exogenous AHLs (3-oxo-C6HSL). Interestingly, the extracts of Vachellia gerrardii (Benth.) P.J.H.Hurter (synonym of Acacia gerrardii Benth) and Elaeodendron buchananii (Loes.) Loes. barks, at 1000 µg/mL reduce the reporter GFP expression (up to 50% inhibition) without any effect on the E. coli biofilm formation [30]. In the same line, two Ethiopian antimicrobial medicinal plants have been reported to exert anti-QS without affecting bacterial viability; the root methanolic extract of Albizia schimperiana Oliv. (Fabaceae) and seed petroleum ether extract of Justicia schimperiana (Hochst. ex Nees) T. Anderson (Acanthaceae) at 6500 µg/mL interfere with cell-to-cell communication, most likely by interacting with the 3-oxo-C6-HSL signaling pathway in E. coli reporter strain AI1-QQ.1 [31].

    For almost 10 years, antivirulence activities of endemic plants from Madagascar have been regularly reported. Indeed, the bark of D. pervillei Vakte and D. trichocarpa Baker (Fabaceae; hexane extracts tested at 300 µg/mL) inhibit the production of P. aeruginosa virulence factors pyocyanin and elastase by 43% and 25%, respectively, and the expression of QS-related (lasI, lasR, rhlI, and rhlR) and QS-regulated (lasB and rhlA) genes [32]. Further investigations on the hexane bark extract of D. trichocarpa, traditionally used to treat various ailments—such as laryngitis, diarrhea, and rheumatic pains—led to the generation of active fractions which exert anti-QS and/or antibiofilm activities. Particularly, an active fraction exerts antibiofilm activities at 200 µg/mL (63% inhibition) without affecting bacterial viability or QS mechanism of P. aeruginosa PAO1. The inhibition of biofilm formation is probably linked to a reduction in flagellar-dependent motilities (swimming and swarming) as well as in exopolysaccharides production [33]. In Madagascar, a mixture of Tephrosia purpurea L. (Fabaceae) and Buddleja madagascariensis Lam (Buddlejaceae) macerated in cow dung manure is traditionally used as a phytotreatment against potato crops diseases such as potato leaf spots caused by the phytophatogen R. solanacearum [34]. The study of their antibacterial effects demonstrated that the methanolic extracts of both plants, tested at 100 µg/mL, reduce the expression of P. aeruginosa PAO1 QS-regulated lasB (45% and 52% inhibition, respectively) and rhlA (32% and 33% inhibition, respectively) genes; but only T. purpurea extracts exhibit antibiofilm activities against P. aeruginosa PAO1 and R. solanacearum (52% and 30% inhibition, respectively) without affecting bacterial growth [35].

    Finally, the dichloromethane extract of Cordia gilletii De Wild (Boraginaceae) root barks, medicinal plant from the Democratic Republic of Congo, a plant known for bactericidal activities against pathogenic microorganisms such as E. coli [36], was also found to quench the production of pyocyanin, to inhibit the expression of several QS-regulated genes (i.e., lasB, rhlA, lasI, lasR, rhlI, and rhlR; 35%, 40%, 24%, 25%, 52%, and 23% inhibition, respectively) and to reduce biofilm formation (21% inhibition) in P. aeruginosa PAO1 without affecting its viability [37].

    2.2. Activities on Gram-Positive Bacteria

    To date, only South African plants have been investigated for their antivirulence activities against Gram-positive bacteria:

    (i) the extracts (concentration, 330 µg/mL) from Cenchrus ciliaris L. (bark; methanol; Poaceae), Eucomis autumnalis (Mill.) Chitt. (bulb; methanol; Asparagaceae), Hypoxis hemerocallidea Fisch., C.A.Mey. & Avé-Lall. (corme; dichloromethane; Hypoxidaceae), Bacharoides adoensis (Sch.Bip. ex Walp.) H.Rob. [synonym of Vernonia adoensis Sch. Bip. ex Walp.] (bark; water; Asteraceae), which are all used to treat urinary tract infections, inhibit biofilm formation (by 21–38%) in S. aureus ATCC 25923 [18];

    (ii) the acetone leaves extracts of different Syzygium and Eugenia species at 1000 µg/mL present antibiofilm activities against S. aureus ATCC 29213, E. faecalis ATCC 29212, and B. cereus ATCC 21366 [17]. Particularly, the extract of S. gerrardii (Harv. ex Hook.f.) Burtt Davy had the capacity to reduce biofilm formation in all tested strains (68–100% inhibition) and to destroy pre-formed biofilms (69–100% biofilm dispersion);

    (iii) the dichloromethane/methanol extracts of plants traditionally used to treat oral infections, including Vachellia karroo (Hyane) Banfi & Galasso (synonym of Acacia karroo Hayne) (leaves; Fabaceae), Erythrina lysistemon Hutch (bark; Fabaceae), Spyrostachys africana Sond. (leaves; Euphorbiaceae), Tecoma capensis (Thumb.) Lindl., (leaves; Bignoniaceae) and Tarchonanthus camphoratus L. (leaves; Asteraceae), at a concentration of 250 µg/mL, showed antibiofilm activity against S. mutans ATCC 25175, known to be responsible for dental caries, with 59%, 68%, 86%, 52%, and 54% inhibition, respectively [38];

    (iv) when the L. monocytogenes ATCC 19111 is grown in the presence of 1000 µg/mL of dichloromethane/methanol leaves extract of Agathosma betulina (P.J. Bergius) Pillans, (Rutaceae), and Aspalathus linearis (Burm.f.) R. Dahlgren (Fabaceae), plants exclusively found in South Africa, biofilm formation reduction was observed with an inhibition rate of 20% and 75%, respectively [39].

    3. Compounds isolated from African plants with Antivirulence Activities

    3.1 Activities on Gram negative bacteria

    Several active fractions containing flavonoid-like compounds, obtained from the bark of Combretum albiflorum (Tul.) Jongkind, (Combretaceae), a Madagascar endemic plant [40], were found to inhibit the production of QS-regulated extracellular virulence factors (violacein in C. violaceum CV026 and pyocyanin in P. aeruginosa PAO1) [41]. Among these flavonoids, the flavan-3-ol catechin, at 4 mM in P. aeruginosa PAO1, had a negative impact on the production of violacein (75 % inhibition), pyocyanin (50% inhibition), elastase (30 % of inhibition), on biofilm formation (30 % inhibition) and on the transcription of several QS-related genes (i.e., lasI, lasR, rhlI, rhlR, lasB, and rhlA). Synthetic epicatechin reduces the P. aeruginosa production of pyocyanin (50 % inhibition) and elastase (30 % inhibition) without effect on biofilm formation. By contrast, epicatechin isolated from Ficus sansibarica Warb.(Moraceae), collected in KwaZulu-Natal, South Africa,reduces the adhesion to polystyrene surfaces of Gram negative E. coli ATCC 25922 up to 15 % at 3.4 mM [42].

    The methyl gallate (MG) isolated from the galls (produced on leaves following insect attack) methanol extract of Guiera senegalensis J. F. Gmel (Combretaceae), a traditional burkinabe treatment of cough, dysentery and malaria, has been shown to exert antivirulence activities [43], Methyl gallate presents MIC values of 512 and 64 µg/mL against P. aeruginosa PAO1 and C. violaceum CV026, respectively, but, at 12.5 µg/mL (67.9 µM), already inhibits the production of pyocyanin (by 65 %) and violacein (by 10 %). These antivirulence activities are in correlation with the data of Hossain et al. [44] who showed that the production of pyocyanin was inhibited (37 - 64 %) by MG in a concentration-dependent manner (16 - 256 μg/mL). Moreover, in P. aeruginosa PAO1, MG reduces the expression of the AHL synthetases genes (lasI and rhlI) and the QS regulator genes (lasR and rhlR) and biofilm formation.

    A triterpenoid coumarate ester has been isolated from Dalbergia trichocarpa Baker(Malagasy endemic species)barkextract as a major bioactive compound. Indeed, oleanolic aldehyde coumarate (OALC), at 200 µM, inhibits the formation of P. aeruginosa PAO1 biofilm (by 44 %) and its maintenance as well as the expression of the las and rhl QS systems [5]. As a consequence, the production of QS-controlled virulence factors, including rhamnolipids, pyocyanin, elastase and extracellular polysaccharides, as well as twitching and swarming motilities are significantly reduced (75 %, 64 %, 19 %, 44 %, 40 % and 52 % inhibition, respectively). Additionally, OALC disorganizes established biofilm structure and significantly increases the bactericidal activity of tobramycin against biofilm-encapsulated PAO1 cells. Consistently, in vivo experiments indicated that OALC treatment reduces P. aeruginosa pathogenicity in Caenorhabditis elegans, a nematode.

    The monocyclic diterpenoid cassipourol and the phytosterol β-sitosterol, isolated from Platostoma rotundifolium (Briq.) A. J. Paton (Lamiaceae), a Burundian anti-infectious plant [45], inhibit QS-regulated and QS-regulatory genes expression in las and rhl systems and disrupt the formation of biofilms by P. aeruginosa at concentrations down to 12.5 and 50 µM, respectively [46]. Authors also isolated α-amyrin, a biosynthesis precursor of ursolic acid [47], that exerts antibiofilm properties at 50 µM without any effect on QS-regulatory genes expression; this suggests that other ursane and oleane-type triterpenes may exert antibiofilm properties with similar mechanisms of action. The three isolated compounds improve swimming but not twitching motilities which consequently promotes planktonic lifestyle in P. aeruginosa PAO1 and dispersal on preformed biofilms. Interestingly, the addition of cassipourol, α-amyrin and β-sitosterol (100 µM) considerably improved the effectiveness of tobramycin (50 µg/mL = 107 µM) against P. aeruginosa PA01 with a drastic reduction in cell viability of biofilm-encapsulated bacteria (89 %, 70 % and 76 % of bacterial death, respectively, versus 40 % in DMSO control treatment).

    4. Discussion

    African plants screened so far provide a clear indication that we have a fairly large source of non-microbicidal natural products active on bacteria. According to literature, the search for antivirulence activities have been shyly initiated since the last decade; by contrast, there has been a wide research on conventional antimicrobial activities (i.e, bactericidal activity) of African plants over the past thirty years [48][49][50]. Although African plants investigated for antivirulence activities are diverse (largely from Southern and Eastern African regions), very few studies have resulted in the characterization of the active compound(s), suggesting that this investigation is only beginning, which highlights a huge potential for new substances still to be discovered. So far however, it should be acknowledged that the discovery of QS modulators has not yet led to major therapeutic breakthroughs; also, QS systems do not control the totality of virulence factors expression and the development of anti-QS bacterial resistance cannot be excluded. But this should not prevent further research in this promising field. Indeed, according to in vitro experiments, the combination of antibiotics and antivirulence (e.g. cassipourol) agents has already demonstrated its potential and about 33 compounds or agents, mainly from synthetic origin, that target virulence factors are under way for preclinical investigations, most of them focusing on P. aeruginosa, Enterobacteriaceae spp. and S. aureus.

    This entry is adapted from 10.3390/antibiotics9110830


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