Antimicrobial Activity of 10 Different Plant Polyphenols against Bacteria Causing Food-Borne Disease. Toshitsugu Taguri Nagasaki Prefectural Institute of Public Health and Environmental Sciences Course of Pharmaceutical Sciences, Nagasaki University Graduate School of Biomedical Sciences Takashi Tanaka Course of Pharmaceutical Sciences, Nagasaki University Graduate School of Biomedical Sciences Isao Kouno Course of Pharmaceutical Sciences, Nagasaki University Graduate School of Biomedical Sciences.

Corresponding author. Keywords: antimicrobial activity test , polyphenol , food-borne pathogenic bacteria , minimum inhibitory concentration. JOURNAL FREE ACCESS.

Published: Received: May 27, Available on J-STAGE: December 01, Accepted: September 06, Advance online publication: - Revised: -. Download PDF K Download citation RIS compatible with EndNote, Reference Manager, ProCite, RefWorks.

Article overview. References Related articles 0. Figures 0. molmol had inhibition diameters of 8. Polygonum aviculare L. The antimicrobial activity of the aqueous, acetone, chloroform, and ethanolic extracts of the stems and leaves of P.

aviculare L. mirabilis, P. typhi, S. paratyphi, S. pyogenes, A. flavus, A. fumigatus, A. albicans Salama and Marraiki, The chloroform extract exhibited the strongest activity followed by the aqueous extract, the ethanol extract, and finally the acetone extract Salama and Marraiki, The chloroform extract had a zone of inhibition diameter between 14 and 28 mm for the stem extract and between 8 and 12 mm for the leaf extract.

No activity was observed against C. albicans in any of the fractions. The stem extracts had a better activity compared to the leaf extract Salama and Marraiki, The antimicrobial activity of the methanol, petroleum ether, chloroform, ethyl acetate, and n -butanol extracts of Chamomilla recutita, Buddleja hybrida , and Glinus lotoides against B.

coli, A. albicans was tested Abdel-Hameed et al. recutita, B. hybrida , and G. lotoides are found in Egypt, and the results of the phytochemical screening shows that alkaloids are only found in the methanolic extract of the three plants, in addition to triterpenes, phenolic compounds, carbohydrates, and saponins Abdel-Hameed et al.

The disk diffusion method results show that the methanolic extract of C. recutita had an activity against E.

coli and C. albicans , with an inhibition zone diameter of 14 mm Abdel-Hameed et al. hybrida exhibited an activity against B. coli , and S. aureus with inhibition zone diameters of 14, 16, and 16 mm, respectively Abdel-Hameed et al.

The methanolic extract of G. lotoides had an activity against B. albicans , with zone of inhibition diameters of 8, 8, 12, 18, and 10 mm, respectively Abdel-Hameed et al. Alkaloids are structurally diverse compounds that have been shown to have antimicrobial activity such as quinolones, metronidazole, or others through inhibiting enzyme activity or other mechanisms.

Many of these alkaloids in plants have not been identified and scientists are currently racing to search for new antimicrobials within this family that may help fight against MDR bacteria.

Antibacterial mechanisms of action differ between different alkaloids. Some examples are reviewed below. Affecting cell division: Phenanthroindolizidine plant alkaloids pergularinine and tylophorinidine inhibit the activity of dihydrofolate reductase, thereby inhibiting nucleic acid synthesis.

Dihydrofolate reductase is an enzyme that is crucial in the production of pyrimidine and purine precursors for amino acids, RNA, and DNA biosynthesis Rao and Venkatachalam, The protein FtsZ is important in bacterial cell division, and it is the prokaryotic homolog of the eukaryotic tubulin.

Berberine, an alkaloid, binds to FtsZ protein with high affinity, causing the inhibition of FtsZ assembly and its GTPase activity, leading to cell elongation, which causes inhibition of cell division Boberek et al.

Ungeremine, an alkaloid, inhibits bacterial E. coli topoisomerases Casu et al. All the naturally occurring quinolone alkaloids are known to lack the 3-carboxy group, which is important for binding and blocking DNA-type IIA topoisomerase complexes Heeb et al. Respiratory inhibition and enzyme inhibition in bacteria.

Moreover, alkyl methyl quinolone alkaloids have a specific and strong antibacterial activity, through respiratory inhibition, against H. pylori Tominaga et al. In addition, agelasine D, a marine sponge diterpene alkaloid, has anti-mycobacterial effect and it exerts its effect by binding directly to BCGc protein, encoded by BCGc , which is a dioxygenase gene, and inhibits its function Arai et al.

Bacterial membrane disruption. Moreover, squalamine, a polyamine alkaloid, acts through a detergent-like mechanism of action against Gram-negative bacteria, leading to the disruption of their outer membranes, and it depolarizes Gram-positive bacterial membranes Alhanout et al.

Affecting virulence genes. ToxT is a regulatory protein found in V. cholerae ; it is directly involved in the activation of many virulence determinants, such as the genes that encode for virulence factors, and the toxin co-regulates pilus and cholera toxin Yang et al.

Virstatin, an isoquinoline alkaloid, inhibits ToxT, leading to the inhibition of the virulence factors. It was also shown to inhibit intestinal colonization of infant mice with V.

cholerae Hung et al. Sortases, membrane-associated transpeptidases in Gram-positive bacteria, have an important role in the adhesion to specific organ tissues, host cell invasion, and the evasion of host-immune response Jang et al. aureus , sortase A has been identified, and strains lacking it are found to be defective in establishing infection.

Aaptamines, an alkaloid, is found to be a sortase A inhibitor Jang et al. Furthermore, isoquinoline alkaloid acts as a sortase inhibitor Kim et al. In addition to that, pyrrolidine Kudryavtsev et al.

Berberine, an alkaloid, inhibits collagenase activity of P. gingivalis and A. actinomycetemcomitans , stopping one of the main factors that lead to the initiation and development of periodontal diseases Hu et al. Furthermore, 2-aminoimidazole Huigens III et al. The susceptibility of microorganisms to antibiotics is affected by phenotypic and genotypic variations in the exposed populations of microorganisms.

The resistance of microorganisms can develop either by the proliferation of previously resistant phenotypes that were underexpressed or as a result of adaptation.

However, the most common cause of antibiotic resistance comes from genetic mutations or genetic mechanisms that allow for the acquisition of genetic information coding-resistant elements Abreu et al.

Bacterial resistance to antibiotics develops through several mechanisms. The most commonly described forms include chemical modification of the antibiotic rendering it inactive, lowering the uptake of the drug, decreasing the accessibility by activating efflux mechanisms, and expressing enzymes that inactivate antibiotics Shin et al.

Plant extracts or phytochemicals are commonly studied as potential resistance-modifying agents RMAs. RMAs have multiple suggested modes of action to restore the effectiveness of antibiotics against resistant bacteria.

Action on modified target sites: a common mechanism of bacterial resistance to antibiotics is modifying the target sites; this occurs with tetracyclins, beta-lactams, and glycopeptides.

Resistance to macrolides, streptogramin B, and lincosamide antibiotics in Streptococcus species is mediated by methylation of the N6 amino in an adenine residue in 23S rRNA Sibanda and Okoh, Resistance to beta-lactams occurs by targeting penicillin-binding protein PBP enzymes in cell walls of the bacteria Abreu et al.

MRSA strains have acquired resistance by obtaining and expressing the mecA gene that codes an altered transpeptidase PBP2a with a lower affinity to penicillin. Inhibiting PBPs would have a significant therapeutic result.

Some agents achieve that either solely or by synergy, acting by blocking targets along the metabolic pathway, thus initiating cell death. Other antibiotics have enhanced activity against PBP2a; those include cephalosporins, trinem, and carbapenems.

A recent example is glycopeptide antibiotics that have activity against vancomycin- and teicoplanin-resistant Gram-positive bacteria Abreu et al. Inhibiting bacterial enzymes that inactivate antibiotics: the most common example of antibiotic inactivation is beta-lactamases that cleave methicillin and related penicillins.

RMAs inhibiting these enzymes protect the antibiotics and prolong their effect. An example would be clavulanic acid, which binds beta-lactamases with high affinity Abreu et al.

This mode of resistance is also employed in Gram-negative bacteria against aminoglycosides Sibanda and Okoh A suppressor of the beta-lactamase operon in S. aureus Blal binds the two regions of dyad symmetry the operators in the blaZ-blaR1 region between genes in a specific manner.

Substituting an N-terminal lysine or a deletion of 23 amino acids will severely impair the repressor's ability to bind DNA; thus both termini are functionally important. Blal repressor binds with similar affinity to upstream regions of the mec gene in methicillin-resistant S.

aureus MRSA , suggesting communication previously observed between the two systems Gregory et al. Membrane permeabilizer agents: resistance to antibiotics may occur in bacteria because of modifying outer membrane proteins OMPs reducing the membrane's permeability to antibiotics.

This form of resistance has been reported in strains resistant to beta-lactams, carbapenems, tetracyclins, sulfonamides, chloremphenicol, and fluoroquinolones. RMAs that disrupt the integrity of the membrane due to their lipophilic nature non-specifically enhance the permeability of the membrane to extracellular compounds including antibiotics Abreu et al.

Galangin, kaempferide, and kaempferideO-beta-D-glucoside were combined with amoxicillin and analyzed against amoxicillin-resistant E. When amoxicillin was combined with any of these flavonoid compounds, a synergistic effect was observed.

Cell count did not go back to normal after 24 h. When galangin was combined with amoxicillin, transmission electron microscopy revealed the detachment of the outer membrane of the cells; a possible mechanism is damage to the internal peptidoglycan layer.

Moreover, some bacteria showed areas of no ribosomes in the cytoplasm. Most treated bacteria appeared larger than control cells. Amoxicillin and kaempferide or kaempferideO-B-D-glucoside had an increased gap between the outer and cytoplasmic membranes. These cells also demonstrated morphological damage to the cell wall and shape.

Several bacteria had broken cell walls. Amoxicillin or flavonoids alone were unable to alter the permeability of the outer membrane in contrast to their combinations.

The effects of combining amoxicillin and kaempferide or kaempferideO-B-D-glucoside were more effective than amoxicillin and galangin Eumkeb et al.

Inhibiting efflux pumps: many of the efflux systems recognize a range of compounds, thus contributing to multidrug resistance Sibanda and Okoh, ; Abreu et al. Although drug efflux systems are expressed constitutively in bacteria, continuous exposure to substrate will cause an upregulation of their expression Terán et al.

Generally, efflux systems can be classified into five families: major facilitator superfamily MFS , resistance-nodulation-division RND family, small multidrug resistance SMR family, ATP binding cassette ABC family, and multiple antibiotic and toxin extrusion MATE family.

Generally, Gram-positive efflux is through MFS, SMR, or ABC, while Gram-negative efflux is through RND and SMR. Some efflux systems have stood out as an important cause of MDR.

These include NorA MDR protein in S. Other active efflux systems in S. aureus are MsrA against macrolides and TetK against tetracycline. Bmr in B. subtilis is active against tetracycline Abreu et al.

MexAB-OprM in P. aeruginosa is the underlying system for resistance against beta-lactams, tetracyclins, trimethoprim, and quinolones; it belongs to the RND family Sibanda and Okoh, ; Abreu et al. Similarly, AcrAB-TolC, from the RND family, in Enterobacteriaceae is responsible for resistance against tetracyclines, chloramphenicol, and fluoroquinolones Abreu et al.

Inhibitors of efflux pumps would restore the susceptibility to antibiotics. Furthermore, another strategy is the synthesis of analogs of antibiotics that the efflux systems are unable to recognize Abreu et al.

A novel efflux inhibitor, GG, is a synthetic inhibitor that was found to be equal to that of reserpine in enhancing the antibiotic activity of norfloxacin and ciprofloxacin against S. In a strain that displayed overexpression of NorA SAB, GG was able to reduce the MICs of the fluoroquinolones by 4- to 8-fold.

These effects were also observed in SA-K that expressed an efflux pump related but distinct to NorA. GG and reserpine were also able to reduce MICs by 2- to 4-fold in control strains susceptible to fluoroquinolones as well as in strains expressing MsrA and TetK, suggesting inhibition of undefined pumps for which norfloxacin and ciprofloxacin are substrates Gibbons et al.

A novel suggestion is the role of sRNAs in the regulation of pathogenic factors in resistant strains. Different sRNAs involved in resistance pathways have been identified.

Hfq, a chaperone protein, is involved in regulating biofilm production and efflux systems, and virulence factors contribute to multidrug resistance pathways. Hfq expression is under the control of sRNAs.

Moreover, in Gram-negative bacteria, expression of OMPs is under the regulation of sRNAs. OMPs are associated with cell-wall targets for antibiotics; they also participate in quorum sensing and facilitate bacterial colonization by affecting the growth of other species.

They also inhibit the immune response of the host by transporting toxins and virulence proteins to host cells Shin et al. Chemical diversity in plants provides a wide source of antibiotic resistance-modifying compounds.

However, most of these compounds act in synergy with intrinsic efflux inhibitors. Thus, these compounds could increase the sensitivity of bacteria to antibiotics. Screening of crude extracts provides the early steps for the isolation of RMAs Sibanda and Okoh, Extract analysis should also take into consideration that these extracts contain complex mixtures of compounds, all of which may add to the final result Abreu et al.

There is considerable evidence that phytochemicals may act as RMAs. It is worth mentioning that the range of action sites that are targeted by plant antibiotics is broader than those derived from microbe-synthesized antibiotics Shin et al. After observing that antibiotics synthesized by plants are generally weaker than those synthesized by bacteria or fungi and that they are generally more active toward Gram-positive bacteria rather than Gram-negative ones, Tegos et al.

Many examples support this hypothesis. In addition, botanic compounds exert antimicrobial effects when combined with microbe-derived antibiotics. Several phytochemicals exhibit antimicrobial actions such as a flavonoid B-ring structure like that of myricetin, robinetin, and epigallocatechin gallate.

The B-ring structure blocks replication in bacterial cells, possibly through hydrogen bonding to the DNA bases. Other flavonoids, like quercetin, block ATPase activity in E.

coli by binding GyrB protein Shin et al. The plant alkaloid reserpine was the first identified inhibitor of the NorA efflux system in S. It demonstrated that it has a similar effect to the disruption of the NorA gene. However, because reserpine has been shown to be neurotoxic at the concentrations required to inhibit NorA efflux system, other inhibitors were researched.

Five new inhibitors of both Bmr and NorA were identified. They were even more potent than reserpine. These inhibitors were able to reverse the ciprofloxacin resistance and decreased the emergence of ciprofloxacin-resistant strains of S.

aureus Markham et al. Shimizu et al. They have also reported that corilagin, a polyphenol, reduced MICs for beta-lactams exclusively by almost to 2,fold. It had a synergistic effect when combined with oxacillin; they were also able to determine that the activity is bactericidal.

Both corilagin and epicatechin gallate were identified as hydrolyzable tannins Shimizu et al. Addition of the extract at sub-MIC concentrations enhanced the effect of tetracycline antibiotics by 2- to 4-fold against Streptococcus sanguis TH, Fusobacterium nucleatum , and S.

oralis SH-2 Al-Hebshi et al. aureus Darwish et al. Nineteen Jordanian plants used in folklore medicine were tested against resistant E. MDR E. coli producing beta-lactamases ESBLs including CTX-M enzymes are an important cause of urinary tract and blood infections.

Generally, methanolic extracts potentiated the inhibitory effects of chloramphenicol, cephalexin, neomycin, doxycycline, and nalidixic acid against both susceptible and resistant strains at a lesser extent. Two plant extracts, Guandelia tournefortii L.

and Pimpinella anisum L. tournefortii L. combined with amoxicillin had anisum L. exhibited Interestingly, Anagryis foetida Lefuminosae and Lepidium sativum Umbelliferae enhanced the effect of amoxicillin against resistant strains but reduced its effect on standard ones.

Erucasativa mill Cruciferae and Origanum syriacum L. Labiateae potentiated clarithromycin against resistant E. coli Darwish and Aburjai, Extracts of R. officinalis L. commonly known as rosemary have shown to have antimicrobial activity.

Carnosol and carnosic acid found in the extract enhanced the activity of tetracycline by 4- and 2-fold, respectively, against an S. aureus strain expressing TetK and carnosic acid; they also decreased the MIC of erythromycin by 8-fold against a strain of S. aureus expressing MsrA. Moreover, carnosic acid inhibited EtBr efflux a substrate for several MDR pumps in an S.

aureus strain expressing NorA Abreu et al. The aqueous extracts of Rosa damascene and R. officinalis reduced MICs of several antibiotics against MRSA and MSSA strains Abreu et al.

Extracts of the native Syrian plant T. spicata L. demonstrated antimicrobial activity against MDR S. aureus and K. pneumoniae strains. Petroleum ether extracts demonstrated activity against MDR strains with MICs of 6.

aureus and When evaluating the synergistic effects of antibiotics, interactions between plant extracts were more effective against resistant strains of S. FIC of cefotaxime combination with antibiotics was 0. The strongest synergism against K. pneumoniae was with ampicillin with FIC ranges of 0.

Ethanolic extracts demonstrated synergism when combined with amikacin against MDR Kp1 and ATCC KP. Furthermore, ethanolic extracts were synergistic with cefotaxime against nine tested strains, with ampicillin against 10, and with amikacin against 8 out of FICs for ampicillin and aqueous extract ranged from 0.

FICs for ampicillin with petroleum ether ranged from 0. Phytochemicals and plant extracts have a promising role in therapeutic applications against MDR bacteria Pandey and Kumar, For instance, menthol, isolated from peppermint oil, was reported to eliminate resistance plasmids in bacteria.

Carbazole alkaloids isolated from Clausena anisate stem bark exhibits strong antifungal and antibacterial activities Pandey and Kumar, Some polyphenol extracts were found to inactivate heat-labile enterotoxin-induced diarrhea Verhelst et al.

Alkaloids mostly exhibit antimicrobial activity through intercalating into the cell wall and DNA of bacteria. In the barks of Cinchona trees, a naturally occurring alkaloid, quinine, is well known as a treatment for malaria Aiyegoro and Okoh, Papaverine, a benzylisoquinoline alkaloid, has a strong inhibitory effect on the replication of cytomegalovirus, human immunodeficient virus, and measles virus Aiyegoro and Okoh, Other than acting as antimicrobials, some of these secondary metabolites can act synergistically with classical antibiotics.

An enhanced antibacterial activity can occur by the synergy of polyphenols with beta-lactams, whereby the former can lead to membrane perturbations and beta-lactams can thus act on the transpeptidase of the cell membrane Aiyegoro and Okoh, Similarly, a combination of root and seed extracts of P.

harmala with novobiocin exhibited a synergistic effect against MRSA, E. anthracis Darabpour et al. When combining these extracts with colistin, a strong antibacterial activity was exhibited even on colistin-resistant E. monocytogenes strains Darabpour et al. Antibiotic resistance has become an increasing source of concern for the health sector.

The first resistant strain of S. aureus was reported in The methicillin-resistant Staphylococcus aureus MRSA are of particular interest. These MDR strains are resistant to almost the entire spectrum of beta-lactams, macrolides, quinolones, and aminoglycosides. MRSA strains are responsible for a high percentage of hospital-acquired infections Abreu et al.

Another major problem is the emergence of antibiotic species causing tuberculosis TB. With ~8. The spread of the tuberculosis was associated with resistance against rifampicin and isoniazid, which are two of the most important drugs to battle TB.

With no new drugs on the market since , the search for Mycobacterium targeting drugs has become an urgent matter Sibanda and Okoh, The use of plant secondary metabolites such as polyphenols or alkaloids has already demonstrated their antimicrobial potential when used alone and as RMAs.

More focus should be given to this field since phytochemicals can act through different mechanisms compared to conventional antibiotics and thus can have the potential in reversing microbial resistance or acting through a pathway different from those of conventional antibiotics.

The diversity in habitats present in the Middle East from hot deserts to cold mountain peaks allows a wide spectrum of plants with more than 20, different species that makes it an optimal place to search for new antimicrobials.

LO searched the literature and extracted and collated data on polyphenols. AS conducted research using available literature and extracted and collated data on alkaloids. RA-M contributed to the integration and overall paper compilation and substantial revision.

All the authors read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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