Current Pharmaceutical BiotechnologyCurrent Pharmaceutical BiotechnologyCurrent Pharmaceutical Biotechnology1389-20101873-4316Bentham Science64451210.2174/0113892010271172231108190233BiotechnologyResearch ArticlePotential of Flavonoids as Promising Phytotherapeutic Agents to Combat Multidrug-Resistant InfectionsPathakDeepikainfo@benthamscience.netMazumderAvijitinfo@benthamscience.netDepartment of Pharmacy, Noida Institute of Engineering and Technology (Pharmacy Institute)Department of Pharmacy,, Noida Institute of Engineering and Technology (Pharmacy Institute)0107202425131664169207012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1389-2010/article/view/644512

Background:Considering the limited number of current effective treatments, Multidrug- Resistant (MDR) illnesses have grown to be a serious concern to public health. It has become necessary to look for new antimicrobial drugs because of the emergence of resistance to numerous kinds of antibiotics. The use of flavonoids is one phytotherapeutic strategy that has been researched as a potential remedy for this issue. Secondary plant compounds called flavonoids have been found to have an antibacterial effect against resistant microorganisms.

Objective:This review seeks to give readers a glimpse into contemporary studies on flavonoids' potential to fight MDR infections.

Methods:A systematic search was conducted on electronic databases (PubMed, Scopus, and Google Scholar) using relevant keywords such as flavonoids, MDR infections, antimicrobial activity, and resistance microbes. Studies that investigated the antimicrobial activity of flavonoids against resistant microbes were included in this review.

Results:Most research found that flavonoids have antibacterial efficacy against resistant microorganisms, and some also showed that they have synergistic benefits with traditional antibiotics. The flavonoids quercetin, kaempferol, apigenin, and luteolin were the most often investigated ones. According to research, flavonoids affect microbial gene expression, inhibit microbial enzymes, and disrupt the integrity of microbial cell membranes. Additionally, a few studies have noted the flavonoids' low toxicity and safety.

Conclusion:For the treatment of infections that are resistant to many drugs, flavonoids constitute a promising class of phytotherapeutic agents. To develop flavonoid-based treatment methods for treating MDR illnesses and assess the potential of flavonoids as adjuvants to conventional antimicrobial drugs, more study is required.

Microbial infectionmultidrug resistancecontroltreatmentphytotherapyflavonoidclinical trials.Jain, P.; Bepari, A.K.; Sen, P.K.; Rafe, T.; Imtiaz, R.; Hossain, M.; Reza, H.M. High prevalence of multiple antibiotic resistance in clinical E. coli isolates from Bangladesh and prediction of molecular resistance determinants using WGS of an XDR isolate. Sci. Rep., 2021, 11(1), 22859. doi: 10.1038/s41598-021-02251-w PMID: 34819576Vivas, R.; Barbosa, A.A.T.; Dolabela, S.S.; Jain, S. Multidrug-resistant bacteria and alternative methods to control them: An overview. Microb. Drug Resist., 2019, 25(6), 890-908. doi: 10.1089/mdr.2018.0319 PMID: 30811275Zhai, X.; Wu, G.; Tao, X.; Yang, S.; Lv, L.; Zhu, Y.; Dong, D.; Xiang, H. Success stories of natural product-derived compounds from plants as multidrug resistance modulators in microorganisms. RSC Advances, 2023, 13(12), 7798-7817. doi: 10.1039/D3RA00184A PMID: 36909750Hassoun-Kheir, N.; Stabholz, Y.; Kreft, J.U.; de la Cruz, R.; Romalde, J.L.; Nesme, J.; Sørensen, S.J.; Smets, B.F.; Graham, D.; Paul, M. Comparison of antibiotic-resistant bacteria and antibiotic resistance genes abundance in hospital and community wastewater: A systematic review. Sci. Total Environ., 2020, 743, 140804. doi: 10.1016/j.scitotenv.2020.140804 PMID: 32758846Bokhary, H.; Pangesti, K.N.A.; Rashid, H.; Abd El Ghany, M.; Hill-Cawthorne, G.A. Travel-related antimicrobial resistance: A systematic review. Trop. Med. Infect. Dis., 2021, 6(1), 11. doi: 10.3390/tropicalmed6010011 PMID: 33467065Agyeman, W.Y.; Bisht, A.; Gopinath, A.; Cheema, A.H.; Chaludiya, K.; Khalid, M.; Nwosu, M.; Konka, S.; Khan, S. A systematic review of antibiotic resistance trends and treatment options for hospital-acquired multidrug-resistant infections. Cureus, 2022, 14(10), e29956. doi: 10.7759/cureus.29956 PMID: 36381838Naylor, N.R.; Atun, R.; Zhu, N.; Kulasabanathan, K.; Silva, S.; Chatterjee, A.; Knight, G.M.; Robotham, J.V. Estimating the burden of antimicrobial resistance: A systematic literature review. Antimicrob. Resist. Infect. Control, 2018, 7(1), 58. doi: 10.1186/s13756-018-0336-y PMID: 29713465Shriram, V.; Kumar, V.; Dey, A. Fighting antimicrobial resistance with natural products - current developments and future prospects. Curr. Top. Med. Chem., 2022, 22(13), 1045. doi: 10.2174/156802662213220630121857 PMID: 35974672Alnour, T.M.S.; Ahmed-Abakur, E.H.; Elssaig, E.H.; Abuduhier, F.M.; Ullah, M.F. Antimicrobial synergistic effects of dietary flavonoids rutin and quercetin in combination with antibiotics gentamicin and ceftriaxone against E. coli (MDR) and P. mirabilis (XDR) strains isolated from human infections: Implications for food–medicine interactions. Ital. J. Food Sci., 2022, 34(2), 34-42. doi: 10.15586/ijfs.v34i2.2196Husain, S.A.; Ahmad, S.; Abass, S.; Parveen, R.; Irfan, M.; Jan, B. Synergy based extracts of medicinal plants: Future antimicrobials to combat multidrug resistance. Curr. Pharm. Biotechnol., 2022, 23(13), 1527-1540. doi: 10.2174/1389201023666220126115656 PMID: 35081888Kumar, S.; Pandey, A.K. Chemistry and biological activities of flavonoids: An overview. ScientificWorldJournal, 2013, 2013, 1-16. doi: 10.1155/2013/162750 PMID: 24470791Cushnie, T.P.T.; Lamb, A.J. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents, 2005, 26(5), 343-356. doi: 10.1016/j.ijantimicag.2005.09.002 PMID: 16323269Shamsudin, N.F.; Ahmed, Q.U.; Mahmood, S.; Ali Shah, S.A.; Khatib, A.; Mukhtar, S.; Alsharif, M.A.; Parveen, H.; Zakaria, Z.A. Antibacterial effects of flavonoids and their structure-activity relationship study: A comparative interpretation. Molecules, 2022, 27(4), 1149. doi: 10.3390/molecules27041149 PMID: 35208939Bell, B.G.; Schellevis, F.; Stobberingh, E.; Goossens, H.; Pringle, M. A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect. Dis., 2014, 14(1), 13. doi: 10.1186/1471-2334-14-13 PMID: 24405683Osei Sekyere, J. Candida auris: A systematic review and meta‐analysis of current updates on an emerging multidrug‐resistant pathogen. MicrobiologyOpen, 2018, 7(4), e00578. doi: 10.1002/mbo3.578 PMID: 29345117Lopo, I.; Libânio, D.; Pita, I.; Dinis-Ribeiro, M.; Pimentel-Nunes, P. Helicobacter pylori antibiotic resistance in Portugal: Systematic review and meta‐analysis. Helicobacter, 2018, 23(4), e12493. doi: 10.1111/hel.12493 PMID: 29911329Tweldemedhin, M.; Muthupandian, S.; Gebremeskel, T.K.; Mehari, K.; Abay, G.K.; Teklu, T.G.; Dhandapani, R.; Paramasivam, R.; Asmelash, T. Multidrug resistance from a one health perspective in Ethiopia: A systematic review and meta-analysis of literature (2015–2020). One Health, 2022, 14, 100390. doi: 10.1016/j.onehlt.2022.100390 PMID: 35686143Charan, J.; Tank, N.; Reljic, T.; Singh, S.; Bhardwaj, P.; Kaur, R.; Goyal, J.; Kumar, A. Prevalence of multidrug resistance tuberculosis in adult patients in India: A systematic review and meta-analysis. J. Family Med. Prim. Care, 2019, 8(10), 3191-3201. doi: 10.4103/jfmpc.jfmpc_542_19 PMID: 31742141Nasiri, M.J.; Zamani, S.; Pormohammad, A.; Feizabadi, M.M.; Aslani, H.R.; Amin, M.; Halabian, R.; Imani Fooladi, A.A. The reliability of rifampicin resistance as a proxy for multidrug-resistant tuberculosis: A systematic review of studies from Iran. Eur. J. Clin. Microbiol. Infect. Dis., 2018, 37(1), 9-14. doi: 10.1007/s10096-017-3079-4 PMID: 28823010Ahmed, I.; Rabbi, M.B.; Sultana, S. Antibiotic resistance in Bangladesh: A systematic review. Int. J. Infect. Dis., 2019, 80, 54-61. doi: 10.1016/j.ijid.2018.12.017 PMID: 30634043Ding, Y.; Wang, Y.; Hsia, Y.; Sharland, M.; Heath, P.T. Systematic review of carbapenem-resistant Enterobacteriaceae causing neonatal sepsis in China. Ann. Clin. Microbiol. Antimicrob., 2019, 18(1), 36. doi: 10.1186/s12941-019-0334-9 PMID: 31727088Solomon, S.L.; Oliver, K.B. Antibiotic resistance threats in the United States: Stepping back from the brink. Am. Fam. Physician, 2014, 89(12), 938-941. PMID: 25162160Infectious Diseases Society of America The 10 x ’20 Initiative: Pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin. Infect. Dis., 2010, 50(8), 1081-1083. doi: 10.1086/652237 PMID: 20214473WHO. WHO publishes list of bacteria for which new antibiotics are urgently needed. 2017. Available From: https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-neededCLSI Performance Standards for Antimicrobial Susceptibility Testing. , 2021. Available From: https://clsi.org/standards/products/microbiology/documents/m100/IDSA New Guidance for Treating Antimicrobial-Resistant Infections Released. , 2021. Available From: https://www.idsociety.org/news--publications-new/articles/2021/new-guidance-for-treating-antimicrobial-resistant-infections-released/Kalil, A.C.; Gilbert, D.N.; Winslow, D.L.; Masur, H.; Klompas, M. Infectious Diseases Society of America (IDSA) POSITION STATEMENT: Why IDSA Did Not Endorse the Surviving Sepsis Campaign Guidelines. Clin. Infect. Dis., 2018, 66(10), 1631-1635. doi: 10.1093/cid/cix997 PMID: 29182749Liu, C.; Bayer, A.; Cosgrove, S.E.; Daum, R.S.; Fridkin, S.K.; Gorwitz, R.J.; Kaplan, S.L.; Karchmer, A.W.; Levine, D.P.; Murray, B.E.; Rybak, M.J.; Talan, D.A.; Chambers, H.F. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin. Infect. Dis., 2011, 52(3), e18-e55. doi: 10.1093/cid/ciq146 PMID: 21208910ESCMID. Guidelines for the Treatment of MDR Bacterial Infections. 2020. Available From: https://www.escmid.org/guidelines/Rhodes, A.; Evans, L.E.; Alhazzani, W.; Levy, M.M.; Antonelli, M.; Ferrer, R.; Kumar, A.; Sevransky, J.E.; Sprung, C.L.; Nunnally, M.E.; Rochwerg, B.; Rubenfeld, G.D.; Angus, D.C.; Annane, D.; Beale, R.J.; Bellinghan, G.J.; Bernard, G.R.; Chiche, J.D.; Coopersmith, C.; De Backer, D.P.; French, C.J.; Fujishima, S.; Gerlach, H.; Hidalgo, J.L.; Hollenberg, S.M.; Jones, A.E.; Karnad, D.R.; Kleinpell, R.M.; Koh, Y.; Lisboa, T.C.; Machado, F.R.; Marini, J.J.; Marshall, J.C.; Mazuski, J.E.; McIntyre, L.A.; McLean, A.S.; Mehta, S.; Moreno, R.P.; Myburgh, J.; Navalesi, P.; Nishida, O.; Osborn, T.M.; Perner, A.; Plunkett, C.M.; Ranieri, M.; Schorr, C.A.; Seckel, M.A.; Seymour, C.W.; Shieh, L.; Shukri, K.A.; Simpson, S.Q.; Singer, M.; Thompson, B.T.; Townsend, S.R.; Van der Poll, T.; Vincent, J.L.; Wiersinga, W.J.; Zimmerman, J.L.; Dellinger, R.P. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit. Care Med., 2017, 45(3), 486-552. doi: 10.1097/CCM.0000000000002255 PMID: 28098591Suganya, T.; Packiavathy, I.A.S.V.; Aseervatham, G.S.B.; Carmona, A.; Rashmi, V.; Mariappan, S.; Devi, N.R.; Ananth, D.A. Tackling multiple-drug-resistant bacteria with conventional and complex phytochemicals. Front. Cell. Infect. Microbiol., 2022, 12, 883839. doi: 10.3389/fcimb.2022.883839 PMID: 35846771Catalano, A.; Iacopetta, D.; Ceramella, J.; Scumaci, D.; Giuzio, F.; Saturnino, C.; Aquaro, S.; Rosano, C.; Sinicropi, M.S. Multidrug resistance (MDR): A widespread phenomenon in pharmacological therapies. Molecules, 2022, 27(3), 616. doi: 10.3390/molecules27030616 PMID: 35163878Gandra, S.; Tseng, K.K.; Arora, A.; Bhowmik, B.; Robinson, M.L.; Panigrahi, B.; Laxminarayan, R.; Klein, E.Y. The mortality burden of multidrug-resistant pathogens in India: A retrospective, observational study. Clin. Infect. Dis., 2019, 69(4), 563-570. doi: 10.1093/cid/ciy955 PMID: 30407501Jubair, N.; Rajagopal, M.; Chinnappan, S.; Abdullah, N.B.; Fatima, A. Review on the antibacterial mechanism of plant-derived compounds against multidrug-resistant bacteria (MDR). Evid. Based Complement. Alternat. Med., 2021, 2021, 1-30. doi: 10.1155/2021/3663315 PMID: 34447454Ugboko, H.U.; Nwinyi, O.C.; Oranusi, S.U.; Fatoki, T.H.; Omonhinmin, C.A. Antimicrobial importance of medicinal plants in Nigeria. ScientificWorldJournal, 2020, 2020, 1-10. doi: 10.1155/2020/7059323 PMID: 33029108Bhatwalkar, S.B.; Mondal, R.; Krishna, S.B.N.; Adam, J.K.; Govender, P.; Anupam, R. Antibacterial Properties of Organosulfur Compounds of Garlic (Allium sativum). Front. Microbiol., 2021, 12, 613077. doi: 10.3389/fmicb.2021.613077 PMID: 34394014Alam, M.; Bano, N.; Ahmad, T.; Sharangi, A.B.; Upadhyay, T.K.; Alraey, Y.; Alabdallah, N.M.; Rauf, M.A.; Saeed, M. Synergistic role of plant extracts and essential oils against multidrug resistance and gram-negative bacterial strains producing extended-spectrum β-lactamases. Antibiotics (Basel), 2022, 11(7), 855. doi: 10.3390/antibiotics11070855 PMID: 35884109Enioutina, E.Y.; Teng, L.; Fateeva, T.V.; Brown, J.C.S.; Job, K.M.; Bortnikova, V.V.; Krepkova, L.V.; Gubarev, M.I.; Sherwin, C.M.T. Phytotherapy as an alternative to conventional antimicrobials: Combating microbial resistance. Expert Rev. Clin. Pharmacol., 2017, 10(11), 1203-1214. doi: 10.1080/17512433.2017.1371591 PMID: 28836870Seukep, A.J.; Kuete, V.; Nahar, L.; Sarker, S.D.; Guo, M. Plant-derived secondary metabolites as the main source of efflux pump inhibitors and methods for identification. J. Pharm. Anal., 2020, 10(4), 277-290. doi: 10.1016/j.jpha.2019.11.002 PMID: 32923005Huang, W.; Wang, Y.; Tian, W.; Cui, X.; Tu, P.; Li, J.; Shi, S.; Liu, X. Biosynthesis investigations of terpenoid, alkaloid, and flavonoid antimicrobial agents derived from medicinal plants. Antibiotics (Basel), 2022, 11(10), 1380. doi: 10.3390/antibiotics11101380 PMID: 36290037Bhatia, P.; Sharma, A.; George, A.J.; Anvitha, D.; Kumar, P.; Dwivedi, V.P.; Chandra, N.S. Antibacterial activity of medicinal plants against ESKAPE: An update. Heliyon, 2021, 7(2), e06310. doi: 10.1016/j.heliyon.2021.e06310 PMID: 33718642Akram, M.; Riaz, M.; Munir, N.; Rasul, A.; Daniyal, M.; Ali Shah, S.M.; Shariati, M.A.; Shaheen, G.; Akhtar, N.; Parveen, F.; Akhter, N.; Owais Ghauri, A.; Chishti, A.W.; Usman Sarwar, M.; Said Khan, F. Progress and prospects in the management of bacterial infections and developments in Phytotherapeutic modalities. Clin. Exp. Pharmacol. Physiol., 2020, 47(7), 1107-1119. doi: 10.1111/1440-1681.13282 PMID: 32064656Shamim, A.; Ali, A.; Iqbal, Z.; Mirza, M.A.; Aqil, M.; Kawish, S.M.; Siddiqui, A.; Kumar, V.; Naseef, P.P.; Alshadidi, A.A.F.; Saheer Kuruniyan, M. Natural medicine a promising candidate in combating microbial biofilm. Antibiotics (Basel), 2023, 12(2), 299. doi: 10.3390/antibiotics12020299 PMID: 36830210Khare, T.; Anand, U.; Dey, A.; Assaraf, Y.G.; Chen, Z.S.; Liu, Z.; Kumar, V. Exploring phytochemicals for combating antibiotic resistance in microbial pathogens. Front. Pharmacol., 2021, 12, 720726. doi: 10.3389/fphar.2021.720726 PMID: 34366872Adamczak, A.; Ożarowski, M.; Karpiński, T.M. Curcumin, a natural antimicrobial agent with strain-specific activity. Pharmaceuticals (Basel), 2020, 13(7), 153. doi: 10.3390/ph13070153 PMID: 32708619Villinski, J.; Dumas, E.; Chai, H.B.; Pezzuto, J.; Angerhofer, C.; Gafner, S. Antibacterial activity and alkaloid content of Berberis thunbergii, Berberis vulgaris and Hydrastis canadensis. Pharm. Biol., 2003, 41(8), 551-557. doi: 10.1080/13880200390500768González de Llano, D.; Moreno-Arribas, M.V.; Bartolomé, B. Cranberry polyphenols and prevention against urinary tract infections: relevant considerations. Molecules, 2020, 25(15), 3523. doi: 10.3390/molecules25153523 PMID: 32752183Nabavi, S.; Di Lorenzo, A.; Izadi, M.; Sobarzo-Sánchez, E.; Daglia, M.; Nabavi, S. Antibacterial effects of cinnamon: From farm to food, cosmetic and pharmaceutical industries. Nutrients, 2015, 7(9), 7729-7748. doi: 10.3390/nu7095359 PMID: 26378575Liu, Q.; Meng, X.; Li, Y.; Zhao, C.N.; Tang, G.Y.; Li, H.B. Antibacterial and antifungal activities of spices. Int. J. Mol. Sci., 2017, 18(6), 1283. doi: 10.3390/ijms18061283 PMID: 28621716Radji, M.; Agustama, R.A.; Elya, B.; Tjampakasari, C.R. Antimicrobial activity of green tea extract against isolates of methicillin–resistant Staphylococcus aureus and multi–drug resistant Pseudomonas aeruginosa. Asian Pac. J. Trop. Biomed., 2013, 3(8), 663-667. doi: 10.1016/S2221-1691(13)60133-1 PMID: 23905026El-Azzouny, M.M.; El-Demerdash, A.S.; Seadawy, H.G.; Abou-Khadra, S.H. Antimicrobial Effect of Garlic (Allium sativum) and Thyme (Zataria multiflora Boiss) extracts on some food borne pathogens and their effect on virulence gene expression. Cell. Mol. Biol., 2018, 64(10), 79-86. doi: 10.14715/cmb/2018.64.10.13 PMID: 30084799Almuhayawi, M.S. Propolis as a novel antibacterial agent. Saudi J. Biol. Sci., 2020, 27(11), 3079-3086. doi: 10.1016/j.sjbs.2020.09.016 PMID: 33100868Wang, L.; Yang, R.; Yuan, B.; Liu, Y.; Liu, C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm. Sin. B, 2015, 5(4), 310-315. doi: 10.1016/j.apsb.2015.05.005 PMID: 26579460Bubonja-Šonje, M.; Knežević, S.; Abram, M. Challenges to antimicrobial susceptibility testing of plant-derived polyphenolic compounds. Archives of Industrial Hygiene and Toxicology, 2020, 71(4), 300-311. doi: 10.2478/aiht-2020-71-3396 PMID: 33410777Silva, E.; Teixeira, J.A.; Pereira, M.O.; Rocha, C.M.R.; Sousa, A.M. Evolving biofilm inhibition and eradication in clinical settings through plant-based antibiofilm agents. Phytomedicine, 2023, 119, 154973. doi: 10.1016/j.phymed.2023.154973 PMID: 37499434Di Lorenzo, C.; Colombo, F.; Biella, S.; Stockley, C.; Restani, P. Polyphenols and human health: The role of bioavailability. Nutrients, 2021, 13(1), 273. doi: 10.3390/nu13010273 PMID: 33477894Solnier, J.; Chang, C.; Pizzorno, J. Consideration for flavonoid-containing dietary supplements to tackle deficiency and optimize health. Int. J. Mol. Sci., 2023, 24(10), 8663. doi: 10.3390/ijms24108663 PMID: 37240008Dias, M.C.; Pinto, D.C.G.A.; Silva, A.M.S. Plant flavonoids: chemical characteristics and biological activity. Molecules, 2021, 26(17), 5377. doi: 10.3390/molecules26175377 PMID: 34500810Zakaryan, H.; Arabyan, E.; Oo, A.; Zandi, K. Flavonoids: Promising natural compounds against viral infections. Arch. Virol., 2017, 162(9), 2539-2551. doi: 10.1007/s00705-017-3417-y PMID: 28547385Ullah, A.; Munir, S.; Badshah, S.L.; Khan, N.; Ghani, L.; Poulson, B.G.; Emwas, A.H.; Jaremko, M. Important flavonoids and their role as a therapeutic agent. Molecules, 2020, 25(22), 5243. doi: 10.3390/molecules25225243 PMID: 33187049Liu, W.; Feng, Y.; Yu, S.; Fan, Z.; Li, X.; Li, J.; Yin, H. The flavonoid biosynthesis network in plants. Int. J. Mol. Sci., 2021, 22(23), 12824. doi: 10.3390/ijms222312824 PMID: 34884627Shen, N.; Wang, T.; Gan, Q.; Liu, S.; Wang, L.; Jin, B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem., 2022, 383, 132531. doi: 10.1016/j.foodchem.2022.132531 PMID: 35413752Nguyen, T.L.A.; Bhattacharya, D. Antimicrobial activity of quercetin: an approach to its mechanistic principle. Molecules, 2022, 27(8), 2494. doi: 10.3390/molecules27082494 PMID: 35458691Wang, S.; Yao, J.; Zhou, B.; Yang, J.; Chaudry, M.T.; Wang, M.; Xiao, F.; Li, Y.; Yin, W. Bacteriostatic effect of quercetin as an antibiotic alternative in vivo and its antibacterial mechanism In vitro. J. Food Prot., 2018, 81(1), 68-78. doi: 10.4315/0362-028X.JFP-17-214 PMID: 29271686Morimoto, Y.; Baba, T.; Sasaki, T.; Hiramatsu, K. Apigenin as an anti-quinolone-resistance antibiotic. Int. J. Antimicrob. Agents, 2015, 46(6), 666-673. doi: 10.1016/j.ijantimicag.2015.09.006 PMID: 26526895Zhou, H.; Xu, M.; Guo, W.; Yao, Z.; Du, X.; Chen, L.; Sun, Y.; Shi, S.; Cao, J.; Zhou, T. The antibacterial activity of kaempferol combined with colistin against colistin-resistant gram-negative bacteria. Microbiol. Spectr., 2022, 10(6), e02265-e22. doi: 10.1128/spectrum.02265-22 PMID: 36314964Duda-Madej, A.; Kozłowska, J.; Krzyżek, P.; Anioł, M.; Seniuk, A.; Jermakow, K.; Dworniczek, E. Antimicrobial O-alkyl derivatives of naringenin and their oximes against multidrug-resistant bacteria. Molecules, 2020, 25(16), 3642. doi: 10.3390/molecules25163642 PMID: 32785151Otsuka, Y. Potent antibiotics active against multidrug-resistant gram-negative bacteria. Chem. Pharm. Bull. (Tokyo), 2020, 68(3), 182-190. doi: 10.1248/cpb.c19-00842 PMID: 32115524Sharma, D.; Yadav, J. An overview of phytotherapeutic approaches for the treatment of tuberculosis. Mini Rev. Med. Chem., 2016, 17(2), 167-183. doi: 10.2174/1389557516666160505114603 PMID: 27145855Yuan, G.; Guan, Y.; Yi, H.; Lai, S.; Sun, Y.; Cao, S. Antibacterial activity and mechanism of plant flavonoids to gram-positive bacteria predicted from their lipophilicities. Sci. Rep., 2021, 11(1), 10471. doi: 10.1038/s41598-021-90035-7 PMID: 34006930Górniak, I.; Bartoszewski, R.; Króliczewski, J. Comprehensive review of antimicrobial activities of plant flavonoids. Phytochem. Rev., 2019, 18(1), 241-272. doi: 10.1007/s11101-018-9591-zFarhadi, F.; Khameneh, B.; Iranshahi, M.; Iranshahy, M. Antibacterial activity of flavonoids and their structure–activity relationship: An update review. Phytother. Res., 2019, 33(1), 13-40. doi: 10.1002/ptr.6208 PMID: 30346068Adamczak, A.; Ożarowski, M.; Karpiński, T.M. Antibacterial activity of some flavonoids and organic acids widely distributed in plants. J. Clin. Med., 2019, 9(1), 109. doi: 10.3390/jcm9010109 PMID: 31906141Santi, M.D.; Ortega, M.G.; Peralta, M.A. A state-of-the-art review and prospective therapeutic applications of prenyl flavonoids as chemosensitizers against antifungal multidrug resistance in Candida albicans. Curr. Med. Chem., 2022, 29(24), 4251-4281. doi: 10.2174/0929867329666220209103538 PMID: 35139777Steinmann, J.; Buer, J.; Pietschmann, T.; Steinmann, E. Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea. Br. J. Pharmacol., 2013, 168(5), 1059-1073. doi: 10.1111/bph.12009 PMID: 23072320Hirose, T.; Ozaki, K.; Saito, Y.; Takai-Todaka, R.; Matsui, H.; Honsho, M.; Iwatsuki, M.; Asami, Y.; Katayama, K.; Sunazuka, T.; Hanaki, H.; Teruya, T. Studies on the Catechin Constituents of Bark of Cinnamomum sieboldii. Chem. Pharm. Bull. (Tokyo), 2023, 71(5), 374-379. doi: 10.1248/cpb.c22-00922 PMID: 37121688Dai, W.; Bi, J.; Li, F.; Wang, S.; Huang, X.; Meng, X.; Sun, B.; Wang, D.; Kong, W.; Jiang, C.; Su, W. Antiviral efficacy of flavonoids against enterovirus 71 infection in vitro and in newborn mice. Viruses, 2019, 11(7), 625. doi: 10.3390/v11070625 PMID: 31284698Fallatah, O.; Georges, E. Apigenin-induced ABCC1-mediated efflux of glutathione from mature erythrocytes inhibits the proliferation of Plasmodium falciparum. Int. J. Antimicrob. Agents, 2017, 50(5), 673-677. doi: 10.1016/j.ijantimicag.2017.08.014 PMID: 28807879Xia, F.; Li, X.; Wang, B.; Gong, P.; Xiao, F.; Yang, M.; Zhang, L.; Song, J.; Hu, L.; Cheng, M.; Sun, C.; Feng, X.; Lei, L.; Ouyang, S.; Liu, Z.J.; Li, X.; Gu, J.; Han, W. Combination therapy of LysGH15 and apigenin as a new strategy for treating pneumonia caused by Staphylococcus aureus. Appl. Environ. Microbiol., 2016, 82(1), 87-94. doi: 10.1128/AEM.02581-15 PMID: 26475103Zhang, D.; Gao, X.; Song, X.; Zhou, W.; Hong, W.; Tian, C.; Liu, Y.; Liu, M. Luteolin showed a resistance elimination effect on gentamicin by decreasing MATE mRNA expression in Trueperella pyogenes. Microb. Drug Resist., 2019, 25(4), 619-626. doi: 10.1089/mdr.2018.0097 PMID: 30431396Liu, C.; Huang, H.; Zhou, Q.; Liu, B.; Wang, Y.; Li, P.; Liao, K.; Su, W. Pithecellobium clypearia extract enriched in gallic acid and luteolin has antibacterial activity against MRSA and reduces resistance to erythromycin, ceftriaxone sodium and levofloxacin. J. Appl. Microbiol., 2020, 129(4), 848-859. doi: 10.1111/jam.14668 PMID: 32301544Jo, S.; Kim, S.; Shin, D.H.; Kim, M.S. Inhibition of SARS-CoV 3CL protease by flavonoids. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 145-151. doi: 10.1080/14756366.2019.1690480 PMID: 31724441Speranta, A.; Manoliu, L.; Sogor, C.; Mernea, M.; Seiman, C.D.; Seiman, D.D.; Chifiriuc, C. Structural bioinformatics used to predict the protein targets of remdesivir and flavones in SARS-CoV-2 Infection. Med. Chem., 2022, 18(3), 382-393. doi: 10.2174/1573406417666210806154129 PMID: 34365955Mayorga, O.A.S.; da Costa, Y.F.G.; da Silva, J.B.; Scio, E.; Ferreira, A.L.P.; de Sousa, O.V.; Alves, M.S. Kalanchoe brasiliensis Cambess., a promising natural source of antioxidant and antibiotic agents against multidrug-resistant pathogens for the treatment of Salmonella Gastroenteritis. Oxid. Med. Cell. Longev., 2019, 2019, 1-15. doi: 10.1155/2019/9245951 PMID: 31827708Meenu, M.T.; Kaul, G.; Shukla, M.; Radhakrishnan, K.V.; Chopra, S. Cudraflavone C from Artocarpus hirsutus as a promising inhibitor of pathogenic, multidrug-resistant S. aureus, persisters, and biofilms: a new insight into a rational explanation of traditional wisdom. J. Nat. Prod., 2021, 84(10), 2700-2708. doi: 10.1021/acs.jnatprod.1c00578 PMID: 34546736Macedo, I.; da Silva, J.H.; da Silva, P.T.; Cruz, B.G.; do Vale, J.P.C.; Dos Santos, H.S.; Bandeira, P.N.; de Souza, E.B.; Xavier, M.R.; Coutinho, H.D.M.; Braz-Filho, R.; Teixeira, A.M.R. Structural and microbiological characterization of 5-hydroxy-3,7,4′-trimethoxyflavone: A flavonoid isolated from vitex gardneriana schauer leaves. Microb. Drug Resist., 2019, 25(3), 434-438.Dzotam, J.K.; Simo, I.K.; Bitchagno, G.; Celik, I.; Sandjo, L.P.; Tane, P.; Kuete, V. In vitro antibacterial and antibiotic modifying activity of crude extract, fractions and 3′,4′,7-trihydroxyflavone from Myristica fragrans Houtt against MDR Gram-negative enteric bacteria. BMC Complement. Altern. Med., 2018, 18(1), 15. doi: 10.1186/s12906-018-2084-1 PMID: 29334931Bame, J.; Graf, T.; Junio, H.; Bussey, R., III; Jarmusch, S.; El-Elimat, T.; Falkinham, J., III; Oberlies, N.; Cech, R.; Cech, N. Sarothrin from Alkanna orientalis is an antimicrobial agent and efflux pump inhibitor. Planta Med., 2013, 79(5), 327-329. doi: 10.1055/s-0032-1328259 PMID: 23468310Bi, C.; Dong, X.; Zhong, X.; Cai, H.; Wang, D.; Wang, L. Acacetin protects mice from Staphylococcus aureus bloodstream infection by inhibiting the activity of sortase A. Molecules, 2016, 21(10), 1285. doi: 10.3390/molecules21101285 PMID: 27681715Lan, J.E.; Li, X.J.; Zhu, X.F.; Sun, Z.L.; He, J.M.; Zloh, M.; Gibbons, S.; Mu, Q. Flavonoids from Artemisia rupestris and their synergistic antibacterial effects on drug-resistant Staphylococcus aureus. Nat. Prod. Res., 2021, 35(11), 1881-1886. doi: 10.1080/14786419.2019.1639182 PMID: 31303068Verdrengh, M.; Collins, L.V.; Bergin, P.; Tarkowski, A. Phytoestrogen genistein as an anti-staphylococcal agent. Microbes Infect., 2004, 6(1), 86-92. doi: 10.1016/j.micinf.2003.10.005 PMID: 14738897Abreu, A.C.; Coqueiro, A.; Sultan, A.R.; Lemmens, N.; Kim, H.K.; Verpoorte, R.; van Wamel, W.J.B.; Simões, M.; Choi, Y.H. Looking to nature for a new concept in antimicrobial treatments: Isoflavonoids from Cytisus striatus as antibiotic adjuvants against MRSA. Sci. Rep., 2017, 7(1), 3777. doi: 10.1038/s41598-017-03716-7 PMID: 28630440Kim, H.; Lee, D.G. Nitric oxide–inducing Genistein elicits apoptosis-like death via an intense SOS response in Escherichia coli. Appl. Microbiol. Biotechnol., 2020, 104(24), 10711-10724. doi: 10.1007/s00253-020-11003-1 PMID: 33170329Singh, V.; Pal, A.; Darokar, M.P. Glabridin synergy with norfloxacin induces ROS in multidrug resistant Staphylococcus aureus. J. Gen. Appl. Microbiol., 2021, 67(6), 269-272. doi: 10.2323/jgam.2021.06.002 PMID: 34690227Yu, J.S.; Kim, J.H.; Rashan, L.; Kim, I.; Lee, W.; Kim, K.H. Potential antimicrobial activity of galloyl-flavonoid glycosides from woodfordia uniflora against methicillin-resistant Staphylococcus aureus. Front. Microbiol., 2021, 12, 784504. doi: 10.3389/fmicb.2021.784504 PMID: 34899667Randhawa, H.K.; Hundal, K.K.; Ahirrao, P.N.; Jachak, S.M.; Nandanwar, H.S. Efflux pump inhibitory activity of flavonoids isolated from Alpinia calcarata against methicillin-resistant Staphylococcus aureus. Biologia (Bratisl.), 2016, 71(5), 484-493. doi: 10.1515/biolog-2016-0073Lin, S.; Li, H.; Tao, Y.; Liu, J.; Yuan, W.; Chen, Y.; Liu, Y.; Liu, S. In vitro and in vivo evaluation of membrane-active flavone amphiphiles: semisynthetic kaempferol-derived antimicrobials against drug-resistant gram-positive bacteria. J. Med. Chem., 2020, 63(11), 5797-5815. doi: 10.1021/acs.jmedchem.0c00053 PMID: 32400157Cruz, B.G.; dos Santos, H.S.; Bandeira, P.N.; Rodrigues, T.H.S.; Matos, M.G.C.; Nascimento, M.F.; de Carvalho, G.G.C.; Braz-Filho, R.; Teixeira, A.M.R.; Tintino, S.R.; Coutinho, H.D.M. Evaluation of antibacterial and enhancement of antibiotic action by the flavonoid kaempferol 7-O-β-D-(6″-O-cumaroyl)-glucopyranoside isolated from Croton piauhiensis müll. Microb. Pathog., 2020, 143, 104144. doi: 10.1016/j.micpath.2020.104144 PMID: 32194182Vipin, C.; Saptami, K.; Fida, F.; Mujeeburahiman, M.; Rao, S.S. Athmika; Arun, A.B.; Rekha, P.D. Potential synergistic activity of quercetin with antibiotics against multidrug-resistant clinical strains of Pseudomonas aeruginosa. PLoS One, 2020, 15(11), e0241304. doi: 10.1371/journal.pone.0241304 PMID: 33156838Vipin, C.; Mujeeburahiman, M.; Ashwini, P.; Arun, A.B.; Rekha, P.D. Anti‐biofilm and cytoprotective activities of quercetin against Pseudomonas aeruginosa isolates. Lett. Appl. Microbiol., 2019, 68(5), 464-471. doi: 10.1111/lam.13129 PMID: 30762887Das, S.; Batra, S.; Gupta, P.P.; Kumar, M.; Srivastava, V.K.; Jyoti, A.; Singh, N.; Kaushik, S. Identification and evaluation of quercetin as a potential inhibitor of naphthoate synthase from Enterococcus faecalis. J. Mol. Recognit., 2019, 32(11), e2802. doi: 10.1002/jmr.2802 PMID: 31353747Kim, M.K.; Lee, T.G.; Jung, M.; Park, K.H.; Chong, Y. In vitro synergism and anti-biofilm activity of quercetin-pivaloxymethyl conjugate against Staphylococcus aureus and Enterococcus Species. Chem. Pharm. Bull. (Tokyo), 2018, 66(11), 1019-1022. doi: 10.1248/cpb.c18-00380 PMID: 30381653Kho, W.; Kim, M.K.; Jung, M.; Chong, Y.P.; Kim, Y.S.; Park, K.H.; Chong, Y. Strain-specific anti-biofilm and antibiotic-potentiating activity of 3′,4′-difluoroquercetin. Sci. Rep., 2020, 10(1), 14162. doi: 10.1038/s41598-020-71025-7 PMID: 32843653Mun, S.H.; Kang, O.H.; Joung, D.K.; Kim, S.B.; Seo, Y.S.; Choi, J.G.; Lee, Y.S.; Cha, S.W.; Ahn, Y.S.; Han, S.H.; Kwon, D.Y. Combination Therapy of Sophoraflavanone B against MRSA: In vitro Synergy Testing. Evid. Based Complement. Alternat. Med., 2013, 2013, 823794. doi: 10.1155/2013/823794Pinto, H.B.; Brust, F.R.; Macedo, A.J.; Trentin, D.S. The antivirulence compound myricetin possesses remarkable synergistic effect with antibacterials upon multidrug resistant Staphylococcus aureus. Microb. Pathog., 2020, 149, 104571. doi: 10.1016/j.micpath.2020.104571 PMID: 33075517Wang, T.; Zhang, P.; Lv, H.; Deng, X.; Wang, J. A natural dietary flavone myricetin as an α-hemolysin inhibitor for controlling Staphylococcus aureus infection. Front. Cell. Infect. Microbiol., 2020, 10, 330. doi: 10.3389/fcimb.2020.00330 PMID: 32793508Motallebi, M.; Khorsandi, K.; Sepahy, A.A.; Chamani, E.; Hosseinzadeh, R. Effect of rutin as flavonoid compound on photodynamic inactivation against P. aeruginosa and S. aureus. Photodiagn. Photodyn. Ther., 2020, 32, 102074. doi: 10.1016/j.pdpdt.2020.102074 PMID: 33137496Alenezi, S.S.; Natto, M.J.; Igoli, J.O.; Gray, A.I.; Fearnley, J.; Fearnley, H.; de Koning, H.P.; Watson, D.G. Novel flavanones with anti-trypanosomal activity isolated from Zambian and Tanzanian propolis samples. Int. J. Parasitol. Drugs Drug Resist., 2020, 14, 201-207. doi: 10.1016/j.ijpddr.2020.10.011 PMID: 33160277Sianglum, W.; Muangngam, K.; Joycharat, N.; Voravuthikunchai, S.P. Mechanism of action and biofilm inhibitory activity of lupinifolin against multidrug-resistant enterococcal clinical isolates. Microb. Drug Resist., 2019, 25(10), 1391-1400. doi: 10.1089/mdr.2018.0391 PMID: 31314663Vijayakumar, K.; Muhilvannan, S.; Arun Vignesh, M. Hesperidin inhibits biofilm formation, virulence and staphyloxanthin synthesis in methicillin resistant Staphylococcus aureus by targeting SarA and CrtM: An In vitro and in silico approach. World J. Microbiol. Biotechnol., 2022, 38(3), 44. doi: 10.1007/s11274-022-03232-5 PMID: 35064842Jeon, D.; Jeong, M.C.; Jnawali, H.; Kwak, C.; Ryoo, S.; Jung, I.; Kim, Y. Phloretin exerts anti-tuberculosis activity and suppresses lung inflammation. Molecules, 2017, 22(1), 183. doi: 10.3390/molecules22010183 PMID: 28117761Gupta, V.K.; Gaur, R.; Sharma, A.; Akther, J.; Saini, M.; Bhakuni, R.S.; Pathania, R. A novel bi-functional chalcone inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of fluoroquinolones. Bioorg. Chem., 2019, 83, 214-225. doi: 10.1016/j.bioorg.2018.10.024 PMID: 30380450Farooq, S.; Wahab, A.T.; Fozing, C.D.A.; Rahman, A.U.; Choudhary, M.I. Artonin I inhibits multidrug resistance in Staphylococcus aureus and potentiates the action of inactive antibiotics in vitro. J. Appl. Microbiol., 2014, 117(4), 996-1011. doi: 10.1111/jam.12595 PMID: 24996035Babii, C.; Savu, M.; Motrescu, I.; Birsa, L.M.; Sarbu, L.G.; Stefan, M. The antibacterial synthetic flavonoid BrCl-Flav exhibits important anti-candida activity by damaging cell membrane integrity. Pharmaceuticals (Basel), 2021, 14(11), 1130. doi: 10.3390/ph14111130 PMID: 34832912Gupta, T.; Kataria, R.; Sardana, S. A comprehensive review on current perspectives of flavonoids as antimicrobial agent. Curr. Top. Med. Chem., 2022, 22(6), 425-434. doi: 10.2174/1568026622666220117104709 PMID: 35040402Chandra, H.; Bishnoi, P.; Yadav, A.; Patni, B.; Mishra, A.; Nautiyal, A. Antimicrobial resistance and the alternative resources with special emphasis on plant-based antimicrobials—a review. Plants, 2017, 6(4), 16. doi: 10.3390/plants6020016 PMID: 28394295Biharee, A.; Sharma, A.; Kumar, A.; Jaitak, V. Antimicrobial flavonoids as a potential substitute for overcoming antimicrobial resistance. Fitoterapia, 2020, 146, 104720. doi: 10.1016/j.fitote.2020.104720 PMID: 32910994Xie, Y.; Yang, W.; Tang, F.; Chen, X.; Ren, L. Antibacterial activities of flavonoids: Structure-activity relationship and mechanism. Curr. Med. Chem., 2014, 22(1), 132-149. doi: 10.2174/0929867321666140916113443 PMID: 25245513Liu, X.W.; Yang, Y.J.; Qin, Z.; Li, S.H.; Bai, L.X.; Ge, W.B.; Li, J.Y. Isobavachalcone from cullen corylifolium presents significant antibacterial activity against clostridium difficile through disruption of the cell membrane. Front. Pharmacol., 2022, 13, 914188. doi: 10.3389/fphar.2022.914188 PMID: 35942219Bhattacharya, D.; Ghosh, D.; Bhattacharya, S.; Sarkar, S.; Karmakar, P.; Koley, H.; Gachhui, R. Antibacterial activity of polyphenolic fraction of Kombucha against Vibrio cholerae: Targeting cell membrane. Lett. Appl. Microbiol., 2018, 66(2), 145-152. doi: 10.1111/lam.12829 PMID: 29193174Liang, H.; He, K.; Li, T.; Cui, S.; Tang, M.; Kang, S.; Ma, W.; Song, L. Mechanism and antibacterial activity of vine tea extract and dihydromyricetin against Staphylococcus aureus. Sci. Rep., 2020, 10(1), 21416. doi: 10.1038/s41598-020-78379-y PMID: 33293561Lee, H.S.; Kim, Y. Myricetin disturbs the cell wall integrity and increases the membrane permeability of Candida albicans. J. Microbiol. Biotechnol., 2022, 32(1), 37-45. doi: 10.4014/jmb.2110.10014 PMID: 34750288Weng, Z.; Zeng, F.; Wang, M.; Guo, S.; Tang, Z.; Itagaki, K.; Lin, Y.; Shen, X.; Cao, Y.; Duan, J.A.; Wang, F. Antimicrobial activities of lavandulylated flavonoids in Sophora flavences against methicillin-resistant Staphylococcus aureus via membrane disruption. J. Adv. Res., 2023, 1232(23), 00123-00126. doi: 10.1016/j.jare.2023.04.017Guo, L.; Li, Y.; Mao, X.; Tao, R.; Tao, B.; Zhou, Z. Antifungal activity of polymethoxylated flavonoids (PMFs)-loaded citral nanoemulsion against penicillium italicum by causing cell membrane damage. J. Fungi (Basel), 2022, 8(4), 388. doi: 10.3390/jof8040388 PMID: 35448619Le, M.T.; Trinh, D.T.T.; Ngo, T.D.; Tran-Nguyen, V.K.; Nguyen, D.N.; Hoang, T.; Nguyen, H.M.; Do, T.G.S.; Mai, T.T.; Tran, T.D.; Thai, K.M. Chalcone derivatives as potential inhibitors of P-glycoprotein and NorA: An In Silico and In vitro Study. BioMed Res. Int., 2022, 2022, 1-9. doi: 10.1155/2022/9982453 PMID: 35378788Pereira, D.; Durães, F.; Szemerédi, N.; Freitas-da-Silva, J.; Pinto, E.; Martins-da-Costa, P.; Pinto, M.; Correia-da-Silva, M.; Spengler, G.; Sousa, E.; Cidade, H. New chalcone–triazole hybrids with promising antimicrobial activity in multidrug resistance strains. Int. J. Mol. Sci., 2022, 23(22), 14291. doi: 10.3390/ijms232214291 PMID: 36430768Jesus, A.; Duraes, F.; Szemeredi, N.; Freitas-Silva, J.; da Costa, P.M.; Pinto, E.; Pinto, M.; Spengler, G.; Sousa, E.; Cidade, H. BDDE-inspired chalcone derivatives to fight bacterial and fungal infections. Mar. Drugs, 2022, 20(5), 315. doi: 10.3390/md20050315Marć, M.A.; Kincses, A.; Rácz, B.; Nasim, M.J.; Sarfraz, M.; Lázaro-Milla, C.; Domínguez-Álvarez, E.; Jacob, C.; Spengler, G.; Almendros, P. Antimicrobial, anticancer and multidrug-resistant reversing activity of novel oxygen-, sulfur- and selenoflavones and bioisosteric analogues. Pharmaceuticals (Basel), 2020, 13(12), 453. doi: 10.3390/ph13120453 PMID: 33322409Holasová, K.; Křížkovská, B.; Hoang, L.; Dobiasová, S.; Lipov, J.; Macek, T.; Křen, V.; Valentová, K.; Ruml, T.; Viktorová, J. Flavonolignans from silymarin modulate antibiotic resistance and virulence in Staphylococcus aureus. Biomed. Pharmacother., 2022, 149, 112806. doi: 10.1016/j.biopha.2022.112806 PMID: 35303568Hellewell, L.; Bhakta, S. Chalcones, stilbenes and ketones have anti-infective properties via inhibition of bacterial drug-efflux and consequential synergism with antimicrobial agents. Access Microbiol., 2020, 2(4), acmi000105. doi: 10.1099/acmi.0.000105 PMID: 33005869Guo, Y.; Huang, C.; Su, H.; Zhang, Z.; Chen, M.; Wang, R.; Zhang, D.; Zhang, L.; Liu, M. Luteolin increases susceptibility to macrolides by inhibiting MsrA efflux pump in Trueperella pyogenes. Vet. Res., 2022, 53(1), 3. doi: 10.1186/s13567-021-01021-w PMID: 35012652Ivanov, M.; Kannan, A.; Stojković, D.S.; Glamočlija, J.; Calhelha, R.C.; Ferreira, I.C.F.R.; Sanglard, D.; Soković, M. Flavones, flavonols, and glycosylated derivatives—impact on Candida albicans growth and virulence, expression of CDR1 and ERG11, cytotoxicity. Pharmaceuticals (Basel), 2020, 14(1), 27. doi: 10.3390/ph14010027 PMID: 33396973Wang, Y.; Su, J.; Zhou, Z.; Yang, J.; Liu, W.; Zhang, Y.; Zhang, P.; Guo, T.; Li, G. Baicalein resensitizes multidrug-resistant gram-negative pathogens to doxycycline. Microbiol. Spectr., 2023, 11(3), e04702-e04722. doi: 10.1128/spectrum.04702-22 PMID: 37070985da Fonseca, S.T.D.; Teixeira, T.R.; Ferreira, J.M.S.; Lima, L.A.R.S.; Luyten, W.; Castro, A.H.F. Flavonoid-rich fractions of Bauhinia holophylla leaves inhibit Candida albicans biofilm formation and hyphae growth. Plants, 2022, 11(14), 1796. doi: 10.3390/plants11141796 PMID: 35890430Li, Y.L.; Chu, Z.Y.; Liu, G.M.; Yang, S.Q.; Zeng, H. The derived components of Gnaphalium hypoleucum DC. Reduce quorum sensing of Chromobacterium violaceum. Molecules, 2022, 27(15), 4881. doi: 10.3390/molecules27154881 PMID: 35956830Wang, L.; Jing, S.; Qu, H.; Wang, K.; Jin, Y.; Ding, Y.; Yang, L.; Yu, H.; Shi, Y.; Li, Q.; Wang, D. Orientin mediates protection against MRSA-induced pneumonia by inhibiting Sortase A. Virulence, 2021, 12(1), 2149-2161. doi: 10.1080/21505594.2021.1962138 PMID: 34369293Wang, S.; Feng, Y.; Han, X.; Cai, X.; Yang, L.; Liu, C.; Shen, L. Inhibition of virulence factors and biofilm formation by wogonin attenuates pathogenicity of Pseudomonas aeruginosa PAO1 via targeting pqs quorum-sensing system. Int. J. Mol. Sci., 2021, 22(23), 12699. doi: 10.3390/ijms222312699 PMID: 34884499Li, M.; Wang, Y.; Jin, J.; Dou, J.; Guo, Q.; Ke, X.; Zhou, C.; Guo, M. Inhibitory activity of honeysuckle extracts against influenza A Virus In vitro and In vivo. Virol. Sin., 2021, 36(3), 490-500. doi: 10.1007/s12250-020-00302-6 PMID: 33044658Kan, J.W.Y.; Yan, C.S.W.; Wong, I.L.K.; Su, X.; Liu, Z.; Chan, T.H.; Chow, L.M.C. Discovery of a flavonoid FM04 as a potent inhibitor to reverse P-glycoprotein-mediated drug resistance in xenografts and improve oral bioavailability of paclitaxel. Int. J. Mol. Sci., 2022, 23(23), 15299. doi: 10.3390/ijms232315299 PMID: 36499627Dao, T.B.N.; Nguyen, T.M.T.; Nguyen, V.Q.; Tran, T.M.D.; Tran, N.M.A.; Nguyen, C.H.; Nguyen, T.H.T.; Nguyen, H.H.; Sichaem, J.; Tran, C.L.; Duong, T.H. Flavones from Combretum quadrangulare growing in vietnam and their alpha-glucosidase inhibitory activity. Molecules, 2021, 26(9), 2531. doi: 10.3390/molecules26092531 PMID: 33926133Gallique, M.; Wei, K.; Maisuria, V.B.; Okshevsky, M.; McKay, G.; Nguyen, D.; Tufenkji, N. Cranberry-derived proanthocyanidins potentiate β-lactam antibiotics against resistant bacteria. Appl. Environ. Microbiol., 2021, 87(10), e00127-e21. doi: 10.1128/AEM.00127-21 PMID: 33712420Jing, S.; Kong, X.; Wang, L.; Wang, H.; Feng, J.; Wei, L.; Meng, Y.; Liu, C.; Chang, X.; Qu, Y.; Guan, J.; Yang, H.; Zhang, C.; Zhao, Y.; Song, W. Quercetin reduces the virulence of S. aureus by targeting ClpP to protect mice from MRSA-induced lethal pneumonia. Microbiol. Spectr., 2022, 10(2), e02340-e21. doi: 10.1128/spectrum.02340-21 PMID: 35319277Morimoto, Y.; Aiba, Y.; Miyanaga, K.; Hishinuma, T.; Cui, L.; Baba, T.; Hiramatsu, K. CID12261165, a flavonoid compound as antibacterial agents against quinolone-resistant Staphylococcus aureus. Sci. Rep., 2023, 13(1), 1725. doi: 10.1038/s41598-023-28859-8 PMID: 36720958Khan, S.A.; Khan, S.U. Fozia; Ullah, N.; Shah, M.; Ullah, R.; Ahmad, I.; Alotaibi, A. Isolation, structure elucidation and in silico prediction of potential drug-like flavonoids from Onosma chitralicum targeted towards functionally important proteins of drug-resistant bad bugs. Molecules, 2021, 26(7), 2048. doi: 10.3390/molecules26072048 PMID: 33918531Rauf, A.; Raza, M.; Humayun Khan, M.; Hemeg, H.A.; Al-Awthan, Y.S.; Bahattab, O.; Bawazeer, S.; Naz, S.; Basoglu, F.; Saleem, M.; Khan, M.; Seyyedamirhossein, H.; Mubarak, M.S.; Erdogan Orhan, I. In vitro and in silico studies on clinically important enzymes inhibitory activities of flavonoids isolated from Euphorbia pulcherrima. Ann. Med., 2022, 54(1), 495-506. doi: 10.1080/07853890.2022.2033826 PMID: 35112936Kim, S.R.; Jeong, M.S.; Mun, S.H.; Cho, J.; Seo, M.D.; Kim, H.; Lee, J.; Song, J.H.; Ko, H.J. Antiviral activity of chrysin against influenza virus replication via inhibition of autophagy. Viruses, 2021, 13(7), 1350. doi: 10.3390/v13071350 PMID: 34372556Kong, X.; Wang, B.; Chen, X.; Wang, L.; Wang, X.; Hou, J.; Wei, L.; Sui, L.; Zhang, C.; Guan, J.; Luan, Y.; Wang, W.; Song, W.; Zhao, Y. Hinokiflavone attenuates the virulence of methicillin-resistant Staphylococcus aureus by targeting caseinolytic protease P. Antimicrob. Agents Chemother., 2022, 66(8), e00240-e22. doi: 10.1128/aac.00240-22 PMID: 35862746Peng, L.Y.; Yuan, M.; Wu, Z.M.; Song, K.; Zhang, C.L.; An, Q.; Xia, F.; Yu, J.L.; Yi, P.F.; Fu, B.D.; Shen, H.Q. Anti-bacterial activity of baicalin against APEC through inhibition of quorum sensing and inflammatory responses. Sci. Rep., 2019, 9(1), 4063. doi: 10.1038/s41598-019-40684-6 PMID: 30858423Sass, A.; Slachmuylders, L.; Van Acker, H.; Vandenbussche, I.; Ostyn, L.; Bové, M.; Crabbé, A.; Chiarelli, L.R.; Buroni, S.; Van Nieuwerburgh, F.; Abatih, E.; Coenye, T. Various evolutionary trajectories lead to loss of the tobramycin-potentiating activity of the quorum-sensing inhibitor baicalin hydrate in Burkholderia cenocepacia Biofilms. Antimicrob. Agents Chemother., 2019, 63(4), e02092-e18. doi: 10.1128/AAC.02092-18 PMID: 30670425Coelho, P.; Oliveira, J.; Fernandes, I.; Araújo, P.; Pereira, A.R.; Gameiro, P.; Bessa, L.J. Pyranoanthocyanins interfering with the quorum sensing of Pseudomonas aeruginosa and Staphylococcus aureus. Int. J. Mol. Sci., 2021, 22(16), 8559. doi: 10.3390/ijms22168559 PMID: 34445281Hao, S.; Yang, D.; Zhao, L.; Shi, F.; Ye, G.; Fu, H.; Lin, J.; Guo, H.; He, R.; Li, J.; Chen, H.; Khan, M.F.; Li, Y.; Tang, H. EGCG-mediated potential inhibition of biofilm development and quorum Sensing in Pseudomonas aeruginosa. Int. J. Mol. Sci., 2021, 22(9), 4946. doi: 10.3390/ijms22094946 PMID: 34066609Samarasinghe, S.; Reid, R. AL-Bayati, M. The anti-virulence effect of cranberry active compound proanthocyanins (PACs) on expression of genes in the third-generation cephalosporin-resistant Escherichia coli CTX-M-15 associated with urinary tract infection. Antimicrob. Resist. Infect. Control, 2019, 8(1), 181. doi: 10.1186/s13756-019-0637-9 PMID: 31832181Omer, F.H.; Al-Khafaji, N.S.K.; Al-Alaq, F.T.; Al-Dahmoshi, H.O.M.; Memariani, M.; Saki, M. Synergistic effects of silybin and curcumin on virulence and carbapenemase genes expression in multidrug resistant Klebsiella oxytoca. BMC Res. Notes, 2022, 15(1), 330. doi: 10.1186/s13104-022-06172-3 PMID: 36273212Qi, W.; Qi, W.; Xiong, D.; Long, M. Quercetin: Its antioxidant mechanism, antibacterial properties and potential application in prevention and control of toxipathy. Molecules, 2022, 27(19), 6545. doi: 10.3390/molecules27196545 PMID: 36235082Shorobi, F.M.; Nisa, F.Y.; Saha, S.; Chowdhury, M.A.H.; Srisuphanunt, M.; Hossain, K.H.; Rahman, M.A. Quercetin: A functional food-flavonoid incredibly attenuates emerging and re-emerging viral infections through immunomodulatory actions. Molecules, 2023, 28(3), 938. doi: 10.3390/molecules28030938 PMID: 36770606Al-Khayri, J.M.; Sahana, G.R.; Nagella, P.; Joseph, B.V.; Alessa, F.M.; Al-Mssallem, M.Q. Flavonoids as Potential Anti-Inflammatory Molecules: A Review. Molecules, 2022, 27(9), 2901. doi: 10.3390/molecules27092901 PMID: 35566252Song, X.; Tan, L.; Wang, M.; Ren, C.; Guo, C.; Yang, B.; Ren, Y.; Cao, Z.; Li, Y.; Pei, J. Myricetin: A review of the most recent research. Biomed. Pharmacother., 2021, 134, 111017. doi: 10.1016/j.biopha.2020.111017 PMID: 33338751Vicente, J.; Benedetti, M.; Martelliti, P.; Vázquez, L.; Gentilini, M.V.; Peñaranda Figueredo, F.A.; Nabaes Jodar, M.S.; Viegas, M.; Barquero, A.A.; Bueno, C.A. The flavonoid cyanidin shows immunomodulatory and broad-spectrum antiviral properties, including SARS-CoV-2. Viruses, 2023, 15(4), 989. doi: 10.3390/v15040989 PMID: 37112969Güran, M.; Çakıral, K.; Teralı, K.; Kandemir, T.; Şanlıtürk, G.; Öcal, M.M.; Nagiyev, T.; Köksal, F. Meropenem in combination with baicalein exhibits synergism against extensively drug resistant and pan-drug-resistant Acinetobacter baumannii clinical isolates in vitro. Pathog. Dis., 2023, 81, ftad007. doi: 10.1093/femspd/ftad007 PMID: 37120729Bai, Y.; Wang, W.; Shi, M.; Wei, X.; Zhou, X.; Li, B.; Zhang, J. Novel antibiofilm inhibitor ginkgetin as an antibacterial synergist against Escherichia coli. Int. J. Mol. Sci., 2022, 23(15), 8809. doi: 10.3390/ijms23158809 PMID: 35955943Song, W.; Wang, L.; Zhao, Y.; Lanzi, G.; Wang, X.; Zhang, C.; Guan, J.; Wang, W.; Guo, X.; Meng, Y.; Wang, B.; Zhao, Y. Hibifolin, a natural sortase A inhibitor, attenuates the pathogenicity of Staphylococcus aureus and enhances the antibacterial activity of cefotaxime. Microbiol. Spectr., 2022, 10(4), e00950-e22. doi: 10.1128/spectrum.00950-22 PMID: 35913166Kampoun, T.; Koonyosying, P.; Ruangsuriya, J.; Prommana, P.; Shaw, P.J.; Kamchonwongpaisan, S.; Suwito, H.; Puspaningsih, N.N.T.; Uthaipibull, C.; Srichairatanakool, S. Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against Plasmodium falciparum. PeerJ, 2023, 11, e15187. doi: 10.7717/peerj.15187 PMID: 37131988Okoye, C.O.; Jiang, H.; Wu, Y.; Li, X.; Gao, L.; Wang, Y.; Jiang, J. Bacterial biosynthesis of flavonoids: Overview, current biotechnology applications, challenges, and prospects. J. Cell. Physiol., 2023, jcp.31006. doi: 10.1002/jcp.31006 PMID: 37025076Manzoor, M.F.; Hussain, A.; Sameen, A.; Sahar, A.; Khan, S.; Siddique, R.; Aadil, R.M.; Xu, B. Novel extraction, rapid assessment and bioavailability improvement of quercetin: A review. Ultrason. Sonochem., 2021, 78, 105686. doi: 10.1016/j.ultsonch.2021.105686 PMID: 34358980Thilakarathna, S.; Rupasinghe, H. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients, 2013, 5(9), 3367-3387. doi: 10.3390/nu5093367 PMID: 23989753Ivanov, M.; Novović, K.; Malešević, M.; Dinić, M.; Stojković, D.; Jovčić, B.; Soković, M. Polyphenols as inhibitors of antibiotic resistant bacteria—mechanisms underlying rutin interference with bacterial virulence. Pharmaceuticals (Basel), 2022, 15(3), 385. doi: 10.3390/ph15030385 PMID: 35337182Pi, J.; Wang, J.; Feng, X.; Li, Z.; Liu, Y.; Yang, W.; Zhang, T.; Guo, P.; Liu, Z.; Qi, D. The Flavonoid Components of Scutellaria baicalensis: Biopharmaceutical properties and their improvement using nanoformulation techniques. Curr. Top. Med. Chem., 2023, 23(1), 17-29. doi: 10.2174/1568026623666221128144258 PMID: 36443977Ravetti, S.; Garro, A.G.; Gaitán, A.; Murature, M.; Galiano, M.; Brignone, S.G.; Palma, S.D. Naringin: Nanotechnological strategies for potential pharmaceutical applications. Pharmaceutics, 2023, 15(3), 863. doi: 10.3390/pharmaceutics15030863 PMID: 36986723Zhang, Z.; Li, X.; Sang, S.; McClements, D.J.; Chen, L.; Long, J.; Jiao, A.; Jin, Z.; Qiu, C. Polyphenols as plant-based nutraceuticals: health effects, encapsulation, nano-delivery, and application. Foods, 2022, 11(15), 2189. doi: 10.3390/foods11152189 PMID: 35892774Tian, Y.; Shi, Z.; Ma, H. Research progress on the preparation and application of flavonoid nanocrystals. Zhejiang Da Xue Xue Bao Yi Xue Ban, 2023, 52(3), 338-348. doi: 10.3724/zdxbyxb-2023-0180 PMID: 37476945Pimentel-Moral, S.; Verardo, V.; Robert, P.; Segura-Carretero, A.; Martinez-Ferez, A. 13-Nanoencapsulation strategies applied to maximize target delivery of intact polyphenols.Encapsulations; Grumezescu, A.M., Ed.; Academic Press: Cambridge, Massachusetts, 2016, pp. 559-595. doi: 10.1016/B978-0-12-804307-3.00013-2Batra, P.; Sharma, A.K. Anti-cancer potential of flavonoids: Recent trends and future perspectives. 3 Biotech., 2013, 3(6), 439-459. doi: 10.1007/s13205-013-0117-5Sajid, M.; Channakesavula, C.N.; Stone, S.R.; Kaur, P. Synthetic biology towards improved flavonoid pharmacokinetics. Biomolecules, 2021, 11(5), 754. doi: 10.3390/biom11050754 PMID: 34069975Vaou, N.; Stavropoulou, E.; Voidarou, C.; Tsigalou, C.; Bezirtzoglou, E. Towards advances in medicinal plant antimicrobial activity: A review study on challenges and future perspectives. Microorganisms, 2021, 9(10), 2041. doi: 10.3390/microorganisms9102041 PMID: 34683362Polansky, H.; Javaherian, A.; Itzkovitz, E. Clinical trial of herbal treatment gene-eden-VIR/novirin in oral herpes. J Evid Based Integr Med., 2018, 23, 2515690X18806269. doi: 10.1177/2515690X18806269Margolin, L.; Luchins, J.; Margolin, D.; Margolin, M.; Lefkowitz, S. 20-week study of clinical outcomes of over-the-counter COVID-19 prophylaxis and treatment. J Evid Based Integr Med., 2021, 26, 2515690X211026193.. doi: 10.1177/2515690X211026193Heinz, S.A.; Henson, D.A.; Austin, M.D.; Jin, F.; Nieman, D.C. Quercetin supplementation and upper respiratory tract infection: A randomized community clinical trial. Pharmacol. Res., 2010, 62(3), 237-242. doi: 10.1016/j.phrs.2010.05.001 PMID: 20478383Pár, A.; Roth, E.; Miseta, A.; Hegedüs, G.; Pár, G.; Hunyady, B.; Vincze, A. Effects of supplementation with the antioxidant flavonoid, silymarin, in chronic hepatitis C patients treated with peg-interferon + ribavirin. A placebo-controlled double blind study Orv. Hetil., 2009, 150(2), 73-79. doi: 10.1556/oh.2009.28517 PMID: 19103558Yao, W.; Zhang, X.; Xu, F.; Cao, C.; Liu, T.; Xue, Y. The therapeutic effects of naringenin on bronchial pneumonia in children. Pharmacol. Res. Perspect., 2021, 9(4), e00825. doi: 10.1002/prp2.825 PMID: 34310866Braun, D.L.; Rauch, A.; Aouri, M.; Durisch, N.; Eberhard, N.; Anagnostopoulos, A.; Ledergerber, B.; Müllhaupt, B.; Metzner, K.J.; Decosterd, L.; Böni, J.; Weber, R.; Fehr, J. A lead-in with silibinin prior to triple-therapy translates into favorable treatment outcomes in difficult-to-treat HIV/Hepatitis C coinfected patients. PLoS One, 2015, 10(7), e0133028. doi: 10.1371/journal.pone.0133028 PMID: 26176696Adeyemo, O.; Doi, H.; Rajender Reddy, K.; Kaplan, D.E. Impact of oral silymarin on virus- and non-virus-specific T-cell responses in chronic hepatitis C infection. J. Viral Hepat., 2013, 20(7), 453-462. doi: 10.1111/jvh.12050 PMID: 23730838Maki, K.C.; Kaspar, K.L.; Khoo, C.; Derrig, L.H.; Schild, A.L.; Gupta, K. Consumption of a cranberry juice beverage lowered the number of clinical urinary tract infection episodes in women with a recent history of urinary tract infection. Am. J. Clin. Nutr., 2016, 103(6), 1434-1442. doi: 10.3945/ajcn.116.130542 PMID: 27251185