Journal of Pharmacy And Bioallied Sciences

: 2021  |  Volume : 13  |  Issue : 2  |  Page : 155--162

Antimicrobial potential of naturally occurring bioactive secondary metabolites

Khaled S Allemailem 
 Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia

Correspondence Address:
Dr. Khaled S Allemailem
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah
Saudi Arabia


The use of traditional medicines of natural origin has been prevalent since ancient times globally as the plants produce a great diversity in their secondary metabolites. The naturally occurring bioactive constituents in food and other plant materials have shown widespread attention for their use as alternative medicine to prevent and cure microbial growth with the least toxic manifestations. The inclusion of these contents revealed their crucial role to improve the therapeutic efficacy of the classical drugs against various pathogenic microorganisms. Furthermore, several metabolites have also been explored in combination with antimicrobial agents to overcome the problems associated with drug resistance. This current review discusses the antimicrobial activities of secondary metabolites as well as their role in drug sensitivity against multiple-drug resistant pathogenic microbes.

How to cite this article:
Allemailem KS. Antimicrobial potential of naturally occurring bioactive secondary metabolites.J Pharm Bioall Sci 2021;13:155-162

How to cite this URL:
Allemailem KS. Antimicrobial potential of naturally occurring bioactive secondary metabolites. J Pharm Bioall Sci [serial online] 2021 [cited 2022 Aug 17 ];13:155-162
Available from:

Full Text


The continuous expansion of multiple drug resistance in different microorganisms has made the strict barrier in combating infectious diseases.[1],[2] The inappropriate use of antibiotics has been found as one of the factors for the development of drug resistance in pathogenic bacteria. However, the discovery of new antimicrobial drugs with novel mechanism could be vital, but the wide and constant increase of antimicrobial drug resistance, weaken such developments.[3],[4],[5] As evident from several reports, it has become a serious threat which needs global concern making the different strategies to overcome this problem. Moreover, the toxic manifestation of currently available antibiotics has sparked massive interest to investigate the antimicrobial potential of naturally occurring herbal products.[6],[7],[8] The use of herbal products and the development of effective combinations have opened several opportunities to drug designers.[9],[10],[11],[12]

The plants and their products have been conventionally used in the treatment of several diseases since ancient times in various populations throughout human evolution and continued till the 20th century.[13],[14],[15] However, the outcomes of allopathic medicines showed enormous consideration in the 20th century and the use of traditional medicines was replaced by it. As the allopathic antibiotics became popular, the misconceptions were also developed correspondingly in establishing it as miracle drugs in most of the developed countries. However, the repeated exposure of irrational and incomplete dose regimens of these antimicrobial drugs lost its potential. The studies suggested that the transformation of drug-resistant genes to other cells of microorganisms, play a crucial role in the development of resistance to the respective antibiotics. Subsequently, such transformations are occurred in the pathogens for other antibiotics make them multi-drug resistant (MDR) that are known as “superbugs.”[4],[16],[17],[18] Nevertheless, the developing countries were continued to use these traditional therapeutic methods as the WHO reported that >80% population of these countries depend on naturally occurring herbal drugs due to its cost-effectiveness.[19],[20],[21]

 Antimicrobial Potential of Phytochemicals or Bioactive Compounds

Interestingly, there are several existing antibiotics, i.e., penicillin, cephalosporins, vancomycin, tetracycline, etc. also derived from natural sources.[22],[23] The development of advanced technologies such as high throughput screening methods, molecular docking has enabled the researchers to identify the molecules combating antibiotic resistance.[24] However, the approach of such molecules in clinical practice is limited as these molecules have not been shown the ability to penetrate the cell wall deviate mutational resistance and efflux pump.[25],[26] Therefore, widespread attention has been made among researchers to evaluate the antimicrobial effect of various products of plants' origin. The high throughput screening of herbal products has replaced the traditional way as it utilized the current understandings of genomics, bioinformatics, and synthetic biology as well. The current tools related to drug discovery enable the drug designers in chemical modifications in the structure of certain bioactive secondary metabolites to make it more effective.[27],[28],[29]

The herbal products show a broad range of biological activities depending on the occurrence of several secondary metabolites, i.e., phenolics, alkaloids, saponins, terpenoids, limonoids, polyacetylenes and secoiridoids, and so on. These secondary metabolites are the product of primary metabolism and key components of plants' natural defense mechanisms. The drugs derived from these biologically active secondary metabolites are considered natural antibiotics as they are associated with the breakdown of the cell wall and cell membranes of microorganisms. As a result, cell death is occurred following the release of cellular contents, disruption of protein binding domain , and enzyme activation.[30],[31],[33],[34]


Most of the plants contain different types of phenolic compounds, to protect them from microbial infections, ultraviolet radiations, and chemical stressors. The researchers have studied various polyphenols found fruits and vegetables from different origins against broad range of pathogens. The polyphenols are generally classified into flavonoids and nonflavonoids (phenolic acids).[35],[36] The extracts of Salvia officinalis have been shown as bactericidal and bacteriostatic effects due to the high content of phenolic acids and flavonoids.[37] Phytochemical analyses revealed that the extracts from Eugenia caryophyllata, Mentha piperita, Rosmarinus officinalis, and Prunus avium have been shown antimicrobial potential as they contain phenolic acids, flavonoids, and terpenoids as well. The presence of five phenolic compounds in the ethanolic extract of A. ampeloprasum as phenolic acid, cinnamic acid, p-coumaric acid, catechin, and sinapic acid showed great antimicrobial efficacy against Prunus aeruginosa and Micrococcus spp.[38] Pomegranate (Punica granatum) juice comprises several polyphenols as caffeic acid, gallic acid, and epigalactocatechin 3-gallate (EGCG) has been reported to inhibit the activity of different dental plaque microorganisms.[39],[40] The clove oil contains several phenolic compounds that has been shown to possess strong antifungal potential against opportunistic fungal pathogens such as Candida albicans, Cryptococcus neoformansi, and Aspergillus fumigatus.[41]

 Phenolic Acids

The antimicrobial effects of phenolic acids have seen mainly against Gram-positive bacteria in comparison to Gram-negative. The hydrophobic structures of the outer membrane in Gram-negative bacteria guard them from various hydrophilic antibiotics including phenolic acids. However, the effects of phenolic acids have been observed in inhibiting the growth of some strains of Gram-negative bacteria.[42],[43],[44] The methanolic extracts from the leaves Matricaria aureus, popularly known as golden chamomile has demonstrated significant growth inhibition against Bacillus subtilis, Streptococcus pyogenes, Staphylococcus aureus, and Klebsiella pneumoniae. The antifungal activity of golden chamomile extract was also noticed against several Colletotrichum gleosporoides, Aspergillus niger, and Aspergillus flavus.[45]


The flavonoids are occurred mainly in the fruits, vegetables, nuts, and seeds of edible plants. They are mainly subclassified into flavones, flavonols, flavanones, flavan-3-ol, isoflavone, and anthocyanidins. These flavonoids cover a wide range of secondary metabolites as luteolin, apigenin, diosmetin, chrysoeriol, tangeretin, sinensetin, gardenin, vitexin, baicalein, kaempferol, quercetin, galangin, datiscetin, morin, robinetin, isorhamnetin, tamarixetin, isoctytososide, quercetagetin, myricetin, hesperetin, taxifolin, eriodictyol, naringenin, catechin, epicatechin, genistein, daidzein, coumestrol, cyanidin, delphinidin, pelargonidin, peonidin, and so on.[46],[47] The antimicrobial activities of several flavonoids were investigated against some Gram-positive lactic acid bacteria of intestines, Gram-negative bacteria Escherichia coli CM 871 and Salmonella. The effect of myrecitin showed significant inhibition in the growth of Lactobacillus, while leutolin, pelargonidin, delphinidin as well as cyanidin-3-glucoside, were found to be effective against E. coli.[48] The bioactive constituent, isocytisoside isolated from the leaves of Aquilegia vulgaris has been shown to be effective against Gram-positive, Gram-negative and fungi as well.[49] The different fractions from the leave extract of Combretum erythrophyllum that contained apigenin, genkwanin, rhamnocitrin, kaempherol, quercetina, and rhamnazin were tested against Vibrio cholerae, Enterococcus faecalis, Micrococcus leuteu, and Shigella sonei. All the tested compounds showed significant growth inhibition against V. cholera and E. faecalis. However, rhamocitrin and quercetin also revealed their potential against M. luteus, S. sonei.[50] The plant Marrubium globosum has been used for the treatment of skin and urinary tract infections since ancient times. The methanolic extract of M. globosum contained flavonoids as rutin, naringenin demonstrated the MIC (8 mg/ml) against S. epidermidis and E. faecalis.[51] The high concentration of quercetin and kaempferol in the ethylene acetate extract of Argyreia speciosa showed strong potential against Micobacterium tuberculosis and Klebsiella pneumonie.[52] The kaempherol has been found effective against a broad range of pathogens such as Bacillus cereus, Listeria monocytogenesi and pseudomonas aeruginosa, M. luteus as well.[53],[54] The antimicrobial efficacy of flavone extracted from the fruits of Feijoa sellowiana has been reported against P. aeruginosa, P. mirabilis, Proteus vulgaris as well as Helicobacter pylori.[55] The study showed the antibacterial effect of morin and quercetin extracted from the fruit of psidium guajava commonly known as guava against Salmonella enteritidis, Bacillus cereus as well as numerous foodborne pathogenic bacteria.[56],[57] Thymoquinone is abundantly found in the seeds of Nigella sativa commonly known as black cumin has been shown potent antimicrobial agent against broad range of microrganisms.[58],[59]


Napthoquinones are found in plants, fungi comprise the one of largest groups of secondary metabolites that has been explored for their biological activities widely. Lapachol, and β-lapachone isolated from Tabebuia species are the naphthoquinones that have been reported to inhi bit the activity of C. albicans, Candida tropicalis and Cryptococcus neoformans.[60] The study showed that the broad-spectrum antimicrobial activity of two naphthoquinones, diospyrin, and isodiospyrin extracted from the root of Diospyros picatoria against several pathogenic bacteria.[61] Lapachol and anthraquinones-containing bark extracts of T. impetiginosa showed strong efficacy against H. pylori.[62] The antibacterial potential of 1,4-naphthoquinone sulfides has been shown as 7.6 and 31.3 mg/ml MIC recorded against S. aureus (Gram + ve) and E. coli (Gram–ve). The antifungal activity of 1,4-naphthoquinone sulfides showed decreased (23.4 mg/ml) in comparison to Amphotericin B (31.3 mg/ml) against C. albicans.[63] The efficacy of lawsone (2-hydroxy-1,4-naphthoquinone)-based compound was found more significant in comparison to conventional antibiotics against methicillin-resistant S. aureus (MRSA) in vitro as well as in vivo.[64]


The studies suggested that several types of alkaloids, i.e., piperine, piperidine, quinoline, indole, pyrrolidine, quinazoline, isoquinoline, glyoxaline, lupinane, tropan, phenanthridine, imidazoline, alkaloidal amines, and terpenoid are naturally occurred in the plants.[65],[66] The indol type of alkaloid fractions extracted from Strychnos ptatorum showed growth-inhibiting potential against P. vulgaris, S. aureus, Salmonella typhimurium, V. cholera, M. tuberculosis A. niger and C. albicans as well.[67],[68],[69] Noticeably, each class of alkaloids has been shown different modes of action against the pathogens. The indolizine class of alkaloids such as pergularinine and tylophorinidine, inhibit the nucleic acid synthesis through the inhibition of dihydrofolate reductase.[70] The effect of bisindole alkaloids such as deoxytopsentin and dibromodeoxytopsentin has been shown against MRSA due to its inherent targeting and inhibiting pyruvate kinase.[71] The study revealed that the natural occurring alkaloids, berberine, hydrastine, and candine extracted from Hydrastis candensis inhibited the bacteria through the Quorum quenching effect (QQE. The QQE is applied to control the disease by inhibiting the expression pathogenic genes instead of killing the bacteria.[72] The aqueous extract of Tinospora cordifoila contains several secondary metabolites including alkaloids have been shown to regenerate the weakened immune system and eradicate the systemic candidiasis in experimental animals.[73] The administration of AETC increased the survival and reduced bacterial load in the mice infected with S. typhimurium.[74]

 Organosulphur Compounds

The organosulphur thiosulfinates such as diallyl sufide, diallyl disulfide (DADS), diallyl trisulfide are main secondary metabolites occurred naturally in garlic, have been shown potent inhibitor of various pathogenic bacteria and yeast.[75],[76],[77] DADS has been reported most active constituent, extracted from garlic in the inhibition of microbial growth. Other organosulfur compounds isolated from cabbage, i.e., Dimethyl trisulfide, methyl methanethiosulfinate, and methyl methanethiosulfonate have also showed significant growth inhibition against different bacterial and fungal species.[78],[79] The broad range of sulfur-containing metabolites is found in the large number of edible plants in the form of glucosinolates.[80] The brown mustard contains gluconapin, while white mustard comprises p-hydroxybenzyl glucosinolate. The high content of allyl, methylthiopropyl, and 2-hydroxy 3-butenyl was determined in horseradish, cabbage, and rapeseed, respectively.[81],[82] The antimicrobial activities of glucosinolates were noticed only in their hydrolytic products. As evident from several studies, isothiocyanates; sulforaphane, and benzyl isothiocyanate have been shown potent inhibitor of human pathogenic bacteria. 4-methyl sulfinyl butylisothiocyanate showed broad-spectrum antimicrobial potential.[83],[84]

 Synergistic Effect of Secondary Metabolites

The synergistic interaction of plant extracts or their secondary metabolites with the existing antibiotics has become one of the effective tools for the management of MDR. Several studies showed that the coadministration of plant-derived extracts or bioactive secondary metabolites with the conventional antimicrobial drugs increased the potential of antibiotics.[85] Several studies suggested the different modes of mechanism in the synergism between the phytochemical and antibiotics against different pathogenic microbes including the MDR.[86],[87]

 Synergism against Pathogenic Bacteria

The resistance to antibiotics has been observed in different types of bacteria by producing alternative target molecules as an enzyme or receptors to survive themselves. For example, the production of PB2a in MRSA, along with penicillin-binding proteins (PBPs), decreased the affinity of b-lactam, penicillin, and cephalosporin. Thereby, the cells continue to synthesize peptidoglycan and remain alive, suggested making the alternative strategy to inhibit such other active sites in the resistance.[88],[89] The coadministration of the crude extract of uva-ursi reduced the MIC of oxacillin or cefmitazole against MRCA. The corilagin was identified and isolated as a main bioactive secondary metabolite in uva-ursi, explored in combination with different b-lactams against MRSA that showed MIC up to thousands fold. However, it did not show such reduction in MIC against Methicillin-susceptible S. aureus strains. It showed that the extract of uva-ursi or corilagin targeted PBP2a only instead of PBPs.[90],[91] Similarly, several phenolic compounds, i.e., tiliroside, pinoresinol, magnatriol B, momorcharaside B, etc. have been shown for their synergistic effect with b-lactams by targeting other sites (PBP2a or PBP4) against MRSA.[92]

As b-lactamases catalyze the b-lactam antibiotics, they are recognized as one of the important factors for bacterial resistance. The determination of different secondary metabolites for their drug-metabolizing enzyme inhibiting activity can make a significant impact in the development of the effective combination of phytochemicals and antibiotics against drug resistance for both Gram-positive as well as Gram-negative bacterial species. The clavulanic acid, a potential b-lactamase inhibitor in combination with various b-lactam antibiotics has been used broadly to improve the therapeutic index of the drugs.[93],[94] The bioactive constituents isolated from green tea have been reported to inhibit b-lactamase and restored the drug antibiotic sensitivity in it.[95] The use of several flavonoids such as baicalin and silibinin also has also showed the synergism against these resistant bacterial strains reducing the MIC of the antibiotics.[96],[97]

The development of MDR in the bacterial strains prevents the entry of the antibiotic inside the cells due to lack of specific D2 porins, or the expression of efflux pumps, i.e., MexAB-OprM, MexCD-OprJ, etc.[98],[[99],[100] Several studies suggested the role of different secondary metabolites as efflux pump inhibitors (EPI). The steroidal alkaloid, found in several plant species of family Apocynaceae, known as conessine, has been shown to inhibit the expression of MexAB-OprM and reversed the susceptibility to the respective drugs in P. aeruginosa.[101] It has been also noted the effect of secondary metabolites in the inhibition of efflux pump, only in combination with the respective antibiotics, but not alone. The use of monoterpene, especially (-)-a-Pinene, has been shown to increase the sensitivity of the drugs several folds against different strains of Campylobacter jejuni, but no effect was measured when it was examined alone.[102] The combination of active constituents (berberine and 5'-methoxyhydnocarpin) of the barberry plant blocked the efflux pump effect leading to increased sensitivity to the antibiotic.[103] The exposure of other phytochemicals such as kaempferol-3-O-α-L-(2,4-bis-E-p-coumaroyl) rhamnoside, indirubin, capsaicin, reserpine, carnosol, and carnosic acid have reported to inhibit the efflux transporter NorA of S. aureus.[104],[105],[106],[107],[108] Several studies also suggested the disintegration of the oily outer membrane of Gram-negative bacteria by and caffeic acid to increase permeability and allow the drug at high concentration inside the cells.[98]

 Synergism against Fungal Infections

Phytochemicals have been shown to play an important role against the resistance developed by the upregulation of efflux pump proteins and biofilm formation. The availability of a limited range of antifungal drugs encouraged the researchers to explore different natural bioactive constituents to overcome the resistance.[109],[110] The synergistic effect of garlic extracts was reported to increase the therapeutic efficacy against C. albicans.[111],[112] The MIC of fluconazole was found to be decreased by two-fold by adding the phenolic compound punicalagin against C. albicans.[113] The use of essential oil from Pelargonium graveolens has been shown to augment the potential of etoconazole against Trichophyton spp.[114] The synergistic effect of caffeic acid and its derivatives have also been evaluated to potentiate the effect of fluconazole and nystatin in various combinations against C. albicans.[115] The increased sensitivity of fluconazole was noticed against C. albicans in diabetic mice when the animals were exposed to thymoquinone along with antifungal agents.[116] As suggested from several studies berberine which is an active constituent of Berberis vulgaris, increase the sensitivity of fluconazole against drug-resistant C. albicans. Furthermore, it has been shown to inhibit the expression of fluphenazine activated drug resistance CDR1 gene.[117],[118],[119] Nyasol is one of the main constituents of Chinese herb, Anemarrhena asphodeloides has been shown for its antifungal as well as the synergistic effect with azoles.[120],[121] Curcumin is active constituent of turmeric that has been studied broadly against various diseases. It has been found to augment the generation of ROS and apoptosis against C. albicans when exposed in combination with azoles and polyenes.[122] Eugenol is the main constituent of essential oils from Syzygium aromaticum (clove) has been suggested from several studies to increase the sensitivity of fluconazole against drug-resistant fungal pathogens.[123]


Over the years, the researchers have identified hundreds of secondary metabolites and investigated their activities against different types of pathogens. The possible mode of microbial cell death or growth inhibition by several phytochemicals has been also established. Several studies revealed the potential of different secondary metabolites against microbial infections in vivo without affecting the beneficial bacteria in the gastrointestinal tracts. The phytochemicals were found effective in combination among them or with conventional antibiotics against broad range of microorganisms. Besides, it was also noticed that secondary metabolites can act synergistically and augment the effect of less efficient antibiotics against various pathogens including MDRs. All the possible consequences of secondary metabolites-drug interactions are suggested to be established as not so attention has been paid on this aspect. Finally, all the studies suggest the use of secondary metabolites as alternative medicine or in combination with conventional antimicrobial agents may play an important role in the development of future drugs of the 21st century.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Ferri M, Ranucci E, Romagnoli P, Giaccone V. Antimicrobial resistance: A global emerging threat to public health systems. Crit Rev Food Sci Nutr 2017;57:2857-76.
2Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: A global multifaceted phenomenon. Pathog Glob Health 2015;109:309-18.
4Amábile-Cuevas CF. New antibiotics and new resistance: In many ways, the fight against antibiotic resistance is already lost; Preventing bacterial disease requires thoughtful new approaches. Am Sci 2003;91:138-49.
5Rossolini GM, Arena F, Pecile P, Pollini S. Update on the antibiotic resistance crisis. Curr Opin Pharmacol 2014;18:56-60.
6Lee CR, Cho IH, Jeong BC, Lee SH. Strategies to minimize antibiotic resistance. Int J Environ Res Public Health 2013;10:4274-305.
7Michael CA, Dominey-Howes D, Labbate M. The antimicrobial resistance crisis: Causes, consequences, and management. Front Public Health 2014;2:145.
8Owens RC Jr. Antimicrobial stewardship: Concepts and strategies in the 21st century. Diagn Microbiol Infect Dis 2008;61:110-28.
9Chandra H, Bishnoi P, Yadav A, Patni B, Mishra AP, Nautiyal AR. Antimicrobial resistance and the alternative resources with special emphasis on plant-based antimicrobials-a review. Plants (Basel) 2017;6:16.
10Gupta PD, Birdi TJ. Development of botanicals to combat antibiotic resistance. J Ayurveda Integr Med 2017;8:266-75.
11Mittal RP, Rana A, Jaitak V. Essential oils: An impending substitute of synthetic antimicrobial agents to overcome antimicrobial resistance. Curr Drug Targets 2019;20:605-24.
12Shin J, Prabhakaran VS, Kim KS. The multi-faceted potential of plant-derived metabolites as antimicrobial agents against multidrug-resistant pathogens. Microb Pathog 2018;116:209-14.
13Greathead H. Plants and plant extracts for improving animal productivity. Proc Nutr Soc 2003;62:279-90.
14Patra AK. An overview of antimicrobial properties of different classes of phytochemicals. In: Patra AK, editor. Dietary Phytochemicals and Microbes. Dordrecht, Netherlands: Springer; 2012. p. 1-32.
15Ramawat KG, Dass S, Mathur M. The chemical diversity of bioactive molecules and therapeutic potential of medicinal plants. In: Ramawat KG, editor. Herbal Drugs: Ethnomedicine to Modern Medicine. Berlin, Heidelberg: Springer; 2009. p. 7-32.
16Breithaupt H. The new antibiotics. Nat Biotechnol 1999;17:1165-9.
17Spellberg B, Guidos R, Gilbert D, Bradley J, Boucher HW, Scheld WM, et al. The epidemic of antibiotic-resistant infections: A call to action for the medical community from the infectious diseases society of America. Clin Infect Dis 2008;46:155-64.
18Widayati A, Suryawati S, de Crespigny C, Hiller JE. Knowledge and beliefs about antibiotics among people in Yogyakarta City Indonesia: A cross sectional population-based survey. Antimicrob Resist Infect Control 2012;1:38.
19Bhat BB, Udupa N, Sreedhar D. Herbal products regulations in a few countries-a brief overview. Curr Drug Discov Technol 2019;16:368-71.
20Mahady GB. Global harmonization of herbal health claims. J Nutr 2001;131:1120s-3s.
21Nair R, Kalariya T, Chanda S. Antibacterial activity of some selected Indian medicinal flora. Turk J Biol 2005;29:41-7.
22Calixto JB. The role of natural products in modern drug discovery. Acad Bras Cienc 2019;91 Suppl 3:e20190105.
23Monciardini P, Iorio M, Maffioli S, Sosio M, Donadio S. Discovering new bioactive molecules from microbial sources. Microb Biotechnol 2014;7:209-20.
24Demain AL. Importance of microbial natural products and the need to revitalize their discovery. J Ind Microbiol Biotechnol 2014;41:185-201.
25Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science 2009;325:1089-93.
26Livermore DM. Discovery research: The scientific challenge of finding new antibiotics. J Antimicrob Chemother 2011;66:1941-4.
27Jujjavarapu SE, Dhagat S. In silico discovery of novel ligands for antimicrobial lipopeptides for computer-aided drug design. Probiotics Antimicrob Proteins 2018;10:129-41.
28Amirkia V, Heinrich M. Natural products and drug discovery: A survey of stakeholders in industry and academia. Front Pharmacol 2015;6:237.
29Paytubi S, de La Cruz M, Tormo JR, Martín J, González I, González-Menendez V, et al. A high-throughput screening platform of microbial natural products for the discovery of molecules with antibiofilm properties against salmonella. Front Microbiol 2017;8:326.
30Davies KM, Jibran R, Zhou Y, Albert NW, Brummell DA, Jordan BR, et al. The evolution of flavonoid biosynthesis: A bryophyte perspective. Front Plant Sci 2020;11:7.
31Hatcher CR, Ryves DB, Millett J. The function of secondary metabolites in plant carnivory. Ann Bot 2020;125:399-411.
32Kliebenstein DJ, Osbourn A. Making new molecules-Evolution of pathways for novel metabolites in plants. Curr Opin Plant Biol 2012;15:415-23.
33Kroymann J. Natural diversity and adaptation in plant secondary metabolism. Curr Opin Plant Biol 2011;14:246-51.
34Pichersky E, Gang DR. Genetics and biochemistry of secondary metabolites in plants: An evolutionary perspective. Trends Plant Sci 2000;5:439-45.
35Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: Food sources and bioavailability. Am J Clin Nutr 2004;79:727-47.
36Quideau S, Deffieux D, Douat-Casassus C, Pouységu L. Plant polyphenols: Chemical properties, biological activities, and synthesis. Angew Chem Int Ed Engl 2011;50:586-621.
37Ghorbani A, Esmaeilizadeh M. Pharmacological properties of Salvia officinalis and its components. J Tradit Complement Med 2017;7:433-40.
38Alamri SA, Moustafa MF. Antimicrobial properties of 3 medicinal plants from Saudi Arabia against some clinical isolates of bacteria. Saudi Med J 2012;33:272-7.
39Singh B, Singh JP, Kaur A, Singh N. Phenolic compounds as beneficial phytochemicals in pomegranate (Punica granatum L.) peel: A review. Food Chem 2018;261:75-86.
40Thangavelu A, Elavarasu S, Sundaram R, Kumar T, Rajendran D, Prem F. Ancient seed for modern cure-pomegranate review of therapeutic applications in periodontics. J Pharm Bioallied Sci 2017;9:S11-4.
41Ahmad N, Alam MK, Shehbaz A, Khan A, Mannan A, Hakim SR, et al. Antimicrobial activity of clove oil and its potential in the treatment of vaginal candidiasis. J Drug Target 2005;13:555-61.
42Alakomi HL, Puupponen-Pimiä R, Aura AM, Helander IM, Nohynek L, Oksman-Caldentey KM, et al. Weakening of salmonella with selected microbial metabolites of berry-derived phenolic compounds and organic acids. J Agric Food Chem 2007;55:3905-12.
43Cueva C, Moreno-Arribas MV, Martín-Alvarez PJ, Bills G, Vicente MF, Basilio A, et al. Antimicrobial activity of phenolic acids against commensal, probiotic and pathogenic bacteria. Res Microbiol 2010;161:372-82.
44Merkl R, Hradkova I, Filip V, Smidrkal J, et al. Antimicrobial and antioxidant properties of phenolic acids alkyl esters. Czech J Food Sci 2018;28:275-9.
45Rizwana H. Antimicrobial activity and chemical composition of flowers of matricaria aurea a native herb of Saudi Arabia. Int J Pharmacol 2016;12:576-86.
46Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: An overview. Scientific World J 2013;2013:162750.
47Sarbu LG, Bahrin LG, Babii C, Stefan M, Birsa ML. Synthetic flavonoids with antimicrobial activity: A review. J Appl Microbiol 2019;127:1282-90.
48Puupponen-Pimiä R, Nohynek L, Meier C, Kähkönen M, Heinonen M, Hopia A, et al. Antimicrobial properties of phenolic compounds from berries. J Appl Microbiol 2001;90:494-507.
49Bylka W, Szaufer-Hajdrych M, Matławska I, Goślińska O. Antimicrobial activity of isocytisoside and extracts of Aquilegia vulgaris L. Lett Appl Microbiol 2004;39:93-7.
50Martini ND, Katerere DR, Eloff JN. Biological activity of five antibacterial flavonoids from Combretum erythrophyllum (Combretaceae). J Ethnopharmacol 2004;93:207-12.
51Rigano D, Formisano C, Basile A, Lavitola A, Senatore F, Rosselli S, et al. Antibacterial activity of flavonoids and phenylpropanoids from Marrubium globosum ssp. libanoticum. Phytother Res 2007;21:395-7.
52Habbu PV, MahadevanKM, Shastry RA, Manjunatha H, Antimicrobial activity of flavanoid sulphates and other fractions of Argyreia speciosa (Burm.f) Boj. Indian J Exp Biol 2009;47:121-8.
53Fierascu RC, Georgiev MI, Fierascu I, Ungureanu C, Avramescu SM. Ortan A, et al. Mitodepressive, antioxidant, antifungal and anti-inflammatory effects of wild-growing Romanian native Arctium lappa L. (Asteraceae) and veronica persica poiret (Plantaginaceae). Food Chem Toxicol 2018;111:44-52.
54Kloucek P, Polesny Z, Svobodova B, Vlkova E, Kokoska L. Antibacterial screening of some Peruvian medicinal plants used in Callería district. J Ethnopharmacol 2005;99:309-12.
55Basile A, Conte B, Rigano D, Senatore F, Sorbo S. Antibacterial and antifungal properties of acetonic extract of Feijoa sellowiana fruits and its effect on Helicobacter pylori growth. J Med Food 2010;13:189-95.
56Arima H, Danno G. Isolation of antimicrobial compounds from guava (Psidium guajava L.) and their structural elucidation. Biosci Biotechnol Biochem 2002;66:1727-30.
57Rattanachaikunsopon P, Phumkhachorn P. Contents and antibacterial activity of flavonoids extracted from leaves of Psidium guajava. J Med Plants Res 2010;4:393-6.
58Goyal SN, Prajapati CP, Gore PR, Patil CR, Mahajan UB, Sharma C, et al. Therapeutic potential and pharmaceutical development of thymoquinone: A multitargeted molecule of natural origin. Front Pharmacol 2017;8:656.
59Khan MA. Antimicrobial action of thymoquinone. In: Younus H, editor. Molecular and Therapeutic actions of Thymoquinone: Actions of Thymoquinone. Singapore: Springer; 2018. p. 57-64.
60Guiraud P, Steiman R, Campos-Takaki GM, Seigle-Murandi F, Simeon de Buochberg M. Comparison of antibacterial and antifungal activities of lapachol and beta-lapachone. Planta Med 1994;60:373-4.
61Adeniyi BA, Fong HH, Pezzuto JM, Luyengi L, Odelola HA. Antibacterial activity of diospyrin, isodiospyrin and bisisodiospyrin from the root of Diospyros piscatoria (Gurke) (Ebenaceae). Phytother Res 2000;14:112-7.
62Park BS, Lee HK, Lee SE, Piao XL, Takeoka GR, Wong RY, et al. Antibacterial activity of Tabebuia impetiginosa Martius ex DC (Taheebo) against Helicobacter pylori. J Ethnopharmacol 2006;105:255-62.
63Wellington KW, Nyoka NB, McGaw LJ. Investigation of the antibacterial and antifungal activity of thiolated naphthoquinones. Drug Dev Res 2019;80:386-94.
64Song R, Yu B, Friedrich D, Li J, Shen H, Krautscheid H, et al. Naphthoquinone-derivative as a synthetic compound to overcome the antibiotic resistance of methicillin-resistant S. aureus. Commun Biol 2020;3:529.
65Othman L, Sleiman A, Abdel-Massih RM. Antimicrobial activity of polyphenols and alkaloids in Middle Eastern plants. Front Microbiol 2019;10:911.
66Shen Y, Chen BL, Zhang QX, Zheng YZ, Fu Q. Traditional uses, secondary metabolites, and pharmacology of Celastrus species-A review. J Ethnopharmacol 2019;241:111934.
67Li DD, Xu Y, Zhang DZ, Quan H, Mylonakis E, Hu DD, et al. Fluconazole assists berberine to kill fluconazole-resistant Candida albicans. Antimicrob Agents Chemother 2013;57:6016-27.
68Mittal RP, Jaitak V. Plant-derived natural alkaloids as new antimicrobial and adjuvant agents in existing antimicrobial therapy. Curr Drug Targets 2019;20:1409-33.
69Yu HF, Qin XJ, Ding CF, Wei X, Yang J, Luo JR, et al. Nepenthe-like indole alkaloids with antimicrobial activity from ervatamia Chinensis. Org Lett 2018;20:4116-20.
70Rao KN, Venkatachalam SR. Inhibition of dihydrofolate reductase and cell growth activity by the phenanthroindolizidine alkaloids pergularinine and tylophorinidine: The in vitro cytotoxicity of these plant alkaloids and their potential as antimicrobial and anticancer agents. Toxicol In Vitro 2000;14:53-9.
71Veale CG, Zoraghi R, Young RM, Morrison JP, Pretheeban M, Lobb KA, et al. Synthetic analogues of the marine bisindole deoxytopsentin: Potent selective inhibitors of MRSA pyruvate kinase. J Nat Prod 2015;78:355-62.
72Mohtar M, Johari SA, Li AR, Isa MM, Mustafa S, Ali AM, et al. Inhibitory and resistance-modifying potential of plant-based alkaloids against methicillin-resistant Staphylococcus aureus (MRSA). Curr Microbiol 2009;59:181-6.
73Alrumaihi F, Allemailem KS, Almatroudi A, Alsahli MA, Khan A, Khan MA. Tinospora cordifolia aqueous extract alleviates cyclophosphamide- induced immune suppression, toxicity and systemic candidiasis in immunosuppressed mice: In vivo study in comparison to antifungal drug fluconazole. Curr Pharm Biotechnol 2019;20:1055-63.
74Alsuhaibani S, Khan MA. Immune-stimulatory and therapeutic activity of tinospora cordifolia: Double-edged sword against salmonellosis. J Immunol Res 2017;2017:1787803.
75Rouf R, Uddin SJ, Sarker DK, Islam MT, Ali ES, Shilpi JA, et al. Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data. Trends Food Sci Technol 2020;104:219-34.
76Yamaguchi Y, Kumagai H. Characteristics, biosynthesis, decomposition, metabolism and functions of the garlic odour precursor, S-allyl-L-cysteine sulfoxide. Exp Ther Med 2020;19:1528-35.
77Avato P, Tursil E, Vitali C, Miccolis V, Candido V. Allylsulfide constituents of garlic volatile oil as antimicrobial agents. Phytomedicine 2000;7:239-43.
78Kyung KH, Fleming HP. Antimicrobial activity of sulfur compounds derived from cabbage. J Food Prot 1997;60:67-71.
79Kyung KH, Lee YC. Antimicrobial activities of sulfur compounds derived from s-alk(en)yl-l-cysteine sulfoxides in allium and brassica. Food Rev Int 2001;17:183-98.
80Fahey JW, Zalcmann AT, Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 2001;56:5-51.
81Melrose J. The glucosinolates: A sulphur glucoside family of mustard anti-tumour and antimicrobial phytochemicals of potential therapeutic application. Biomedicines 2019;7:62.
82Paul S, Geng CA, Yang TH, Yang YP, Chen JJ. Phytochemical and health-beneficial progress of turnip (Brassica rapa). J Food Sci 2019;84:19-30.
83Kou X, Li B, Olayanju JB, Drake JM, Chen N. Nutraceutical or pharmacological potential of Moringa oleifera lam. Nutrients 2018;10:343.
84Romeo L, Iori R, Rollin P, Bramanti P, Mazzon E. Isothiocyanates: An overview of their antimicrobial activity against human infections. Molecules 2018;23:624.
85Ayaz M, Ullah F, Sadiq A, Ullah F, Ovais M, Ahmed J, et al. Synergistic interactions of phytochemicals with antimicrobial agents: Potential strategy to counteract drug resistance. Chem Biol Interact 2019;308:294-303.
86Abreu AC, McBain AJ, Simões M. Plants as sources of new antimicrobials and resistance-modifying agents. Nat Prod Rep 2012;29:1007-21.
87Anand U, Nandy S, Mundhra A, Das N, Pandey DK, Dey A. A review on antimicrobial botanicals, phytochemicals and natural resistance modifying agents from apocynaceae family: Possible therapeutic approaches against multidrug resistance in pathogenic microorganisms. Drug Resist Updat 2020;51:100695.
88Algammal AM, Hetta HF, Elkelish A, Alkhalifah DH, Hozzein WN, Batiha GE, et al. Methicillin-resistant Staphylococcus aureus (MRSA): One health perspective approach to the bacterium epidemiology, virulence factors, antibiotic-resistance, and zoonotic impact. Infect Drug Resist 2020;13:3255-65.
89Leonard FC, Markey BK. Meticillin-resistant staphylococcus aureus in animals: A review. Vet J 2008;175:27-36.
90Li X, Deng Y, Zheng Z, Huang W, Chen L, Tong Q, et al. Corilagin, a promising medicinal herbal agent. Biomed Pharmacother 2018;99:43-50.
91Shimizu M, Shiota S, Mizushima T, Ito H, Hatano T, Yoshida T, et al. Marked potentiation of activity of beta-lactams against methicillin-resistant Staphylococcus aureus by corilagin. Antimicrob Agents Chemother 2001;45:3198-201.
92Kuok CF, Hoi SO, Hoi CF, Chan CH, Fong IH, Ngok CK, et al. Synergistic antibacterial effects of herbal extracts and antibiotics on methicillin-resistant Staphylococcus aureus: A computational and experimental study. Exp Biol Med (Maywood) 2017;242:731-43.
93Livermore DM. Beta-lactamases in laboratory and clinical resistance. Clin Microbiol Rev 1995;8:557-84.
94Susić E. Mechanisms of resistance in Enterobacteriaceae towards beta-lactamase antibiotics. Acta Med Croatica 2004;58:307-12.
95Yam TS, Hamilton-Miller JM, Shah S. The effect of a component of tea (Camellia sinensis) on methicillin resistance, PBP2' synthesis, and beta-lactamase production in Staphylococcus aureus. J Antimicrob Chemother 1998;42:211-6.
96Kang HK, Kim HY, Cha JD. Synergistic effects between silibinin and antibiotics on methicillin-resistant Staphylococcus aureus isolated from clinical specimens. Biotechnol J 2011;6:1397-408.
97Liu IX, Durham DG, Richards RM. Baicalin synergy with beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus and other beta-lactam-resistant strains of S. aureus. J Pharm Pharmacol 2000;52:361-6.
98Chopra I. Efflux-based antibiotic resistance mechanisms: The evidence for increasing prevalence. J Antimicrob Chemother 1992;30:737-9.
99Poole K. Multidrug efflux pumps and antimicrobial resistance in Pseudomonas aeruginosa and related organisms. J Mol Microbiol Biotechnol 2001;3:255-64.
100Poole K. Pseudomonas aeruginosa: Resistance to the max. Front Microbiol 2011;2:65.
101Siriyong T, Srimanote P, Chusri S, Yingyongnarongkul BE, Suaisom C, Tipmanee V, et al. Conessine as a novel inhibitor of multidrug efflux pump systems in Pseudomonas aeruginosa. BMC Complement Altern Med 2017;17:405.
102Kovač J, Šimunović K, Wu Z, Klančnik A, Bucar F, Zhang Q, et al. Antibiotic resistance modulation and modes of action of (-)-α-pinene in Campylobacter jejuni. PLoS One 2015;10:e0122871.
103Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K. Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci U S A 2000;97:1433-7.
104Holler JG, Christensen SB, Slotved HC, Rasmussen HB, Gúzman A, Olsen CE, et al. Novel inhibitory activity of the Staphylococcus aureus NorA efflux pump by a kaempferol rhamnoside isolated from Persea lingue Nees. J Antimicrob Chemother 2012;67:1138-44.
105Kalia NP, Mahajan P, Mehra R, Nargotra A, Sharma JP, Koul S, et al. Capsaicin, a novel inhibitor of the NorA efflux pump, reduces the intracellular invasion of Staphylococcus aureus. J Antimicrob Chemother 2012;67:2401-8.
106Oluwatuyi M, Kaatz GW, Gibbons S. Antibacterial and resistance modifying activity of Rosmarinus officinalis. Phytochemistry 2004;65:3249-54.
107Ponnusamy K, Ramasamy M, Savarimuthu I, Paulraj MG. Indirubin potentiates ciprofloxacin activity in the NorA efflux pump of Staphylococcus aureus. Scand J Infect Dis 2010;42:500-5.
108Schmitz FJ, Fluit AC, Lückefahr M, Engler B, Hofmann B, Verhoef J, et al. The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in-vitro activities of ciprofloxacin, sparfloxacin and moxifloxacin against clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 1998;42:807-10.
109Movahed E, Tan GM, Munusamy K, Yeow TC, Tay ST, Wong WF, et al. Triclosan demonstrates synergic effect with amphotericin b and fluconazole and induces apoptosis-like cell death in cryptococcus neoformans. Front Microbiol 2016;7:360.
110Ngo HX, Garneau-Tsodikova S, Green KD. A complex game of hide and seek: The search for new antifungals. Medchemcomm 2016;7:1285-306.
111Salih K. Synergistic effects of plant extracts and antifungal drugs on C. albicans. J Dev Drugs 2016;5:3.
112Zainal M, Zain NM, Amin IM, Ahmad VN. The antimicrobial and antibiofilm properties of allicin against Candida albicans and Staphylococcus aureus – A therapeutic potential for denture stomatitis. The Saudi Dental J 2020;1:1-7.
113Endo EH, Cortez DA, Ueda-Nakamura T, Nakamura CV, Dias Filho BP. Potent antifungal activity of extracts and pure compound isolated from pomegranate peels and synergism with fluconazole against Candida albicans. Res Microbiol 2010;161:534-40.
114Shin S, Lim S. Antifungal effects of herbal essential oils alone and in combination with ketoconazole against Trichophyton spp. J Appl Microbiol 2004;97:1289-96.
115Sardi JC, Gullo FP, Freires IA, Pitangui NS, Segalla MP, Fusco-Almeida AM, et al. Synthesis, antifungal activity of caffeic acid derivative esters, and their synergism with fluconazole and nystatin against Candida spp. Diagn Microbiol Infect Dis 2016;86:387-91.
116Khan MA, Aldebasi YH, Alsuhaibani SA, AlSahli MA, Alzohairy MA, Khan A, et al. Therapeutic potential of thymoquinone liposomes against the systemic infection of Candida albicans in diabetic mice. PLoS One 2018;13:e0208951.
117Dhamgaye S, Devaux F, Vandeputte P, Khandelwal NK, Sanglard D, Mukhopadhyay G, et al. Molecular mechanisms of action of herbal antifungal alkaloid berberine, in Candida albicans. PLoS One 2014;9:e104554.
118Li DD, Xu Y, Zhang DZ, Quan H, Mylonakis E, Hu DD, et al. Fluconazole assists berberine to kill fluconazole-resistant Candida albicans. Antimicrob Agents Chemother 2013;57:6016-27.
119Xu Y, Wang Y, Yan L, Liang RM, Dai BD, Tang RJ, et al. Proteomic analysis reveals a synergistic mechanism of fluconazole and berberine against fluconazole-resistant Candida albicans: Endogenous ROS augmentation. J Proteome Res 2009;8:5296-304.
120Iida Y, Oh KB, Saito M, Matsuoka H, Kurata H. In vitro synergism between nyasol, an active compound isolated from Anemarrhena asphodeloides, and azole agents against Candida albicans. Planta Med 2000;66:435-8.
121Park HJ, Lee JY, Moon SS, Hwang BK. Isolation and anti-oomycete activity of nyasol from Anemarrhena asphodeloides rhizomes. Phytochemistry 2003;64:997-1001.
122Sharma M, Manoharlal R, Negi AS, Prasad R. Synergistic anticandidal activity of pure polyphenol curcumin I in combination with azoles and polyenes generates reactive oxygen species leading to apoptosis. FEMS Yeast Res 2010;10:570-8.
123Ahmad A, Khan A, Khan LA, Manzoor N. In vitro synergy of eugenol and methyleugenol with fluconazole against clinical Candida isolates. J Med Microbiol 2010;59:1178-84.