Herbal extracts as antibiotic adjuvants against ESKAPE pathogens: mechanisms and therapeutic potential

Abstract

The escalating crisis of antimicrobial resistance, particularly driven by ESKAPE pathogens, poses a serious threat to global public health. With the stagnant pipeline of novel antibiotic discovery, repurposing herbal extracts as antibiotic adjuvants to revive existing therapies is a promising strategy. This review systematically elaborates the multi-faceted mechanisms by which herbal extracts and their bioactive constituents counteract multi-drug resistance in ESKAPE pathogens. These mechanisms include the inhibition of antibiotic-degrading enzymes, alteration of bacterial membrane permeability to facilitate antibiotic uptake, blockade of major efflux pumps that expel multiple drug classes, and counteraction of antibiotic target modification. Furthermore, the roles of phytochemicals in inhibiting and dispersing biofilms, attenuating virulence factors, disrupting quorum sensing, and promoting reactive oxygen species accumulation are discussed. Despite the potent synergistic potential demonstrated by various lead compounds (such as andrographolide, quercetin, berberine, thymol, curcumin, eugenol, and oleanolic acid) in preclinical models, their progression through the translational pipeline is frequently hindered by inconsistent manufacturing standards and the inherent complexity of elucidating their polypharmacological mechanisms. Advancing the clinical utility of these herbal adjuvants necessitates a multidimensional approach, including artificial intelligence-driven screening, in-depth mechanistic studies of multi-component synergy, and comprehensive clinical assessments. Accordingly, this review aimed to establish a rigorous foundation for designing next-generation anti-infective therapies based on herb–antibiotic synergy.

Keywords

Herbal / Antibiotic resistance / ESKAPE pathogens / Antibiotic adjuvants / Synergistic effect

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Hanlin Ma: Writing – original draft, Investigation, Data curation. Jing Wang: Validation, Supervision, Funding acquisition. Fengyu Zhang: Funding acquisition. Lichuan Gu: Funding acquisition. Wei Hu: Writing – review & editing, Conceptualization. Chuandong Wang: Writing – review & editing, Writing – original draft, Project administration.

References

[1] G.B.D.A.R. Collaborators, Global burden of bacterial antimicrobial resistance 1990—2021: a systematic analysis with forecasts to 2050, Lancet 404 (2024) 1199-1226.

[2] J.M. Blair, M.A. Webber, A.J. Baylay, D.O. Ogbolu, L.J. Piddock, Molecular mechanisms of antibiotic resistance, Nat. Rev. Microbiol. 13 (2015) 42-51.

[3] W. Su, W. Wang, L. Li, M. Zhang, H. Xu, C. Fu, X. Pang, M. Wang, Mechanisms of tigecycline resistance in gram—negative bacteria: a narrative review, Eng. Microbiol. 4 (2024) 100165.

[4] R. Aggarwal, P. Mahajan, S. Pandiya, A. Bajaj, S.K. Verma, P. Yadav, A.S. Kharat, A.U. Khan, M. Dua, A.K. Johri, Antibiotic resistance: a global crisis, problems and solutions, Crit. Rev. Microbiol. 50 (2024) 896-921.

[5] G.D. Wright, Bacterial resistance to antibiotics: enzymatic degradation and modification, Adv. Drug Deliv. Rev. 57 (2005) 1451-1470.

[6] J. Ma, X. Song, M. Li, Z. Yu, W. Cheng, Z. Yu, W. Zhang, Y. Zhang, A. Shen, H. Sun, L. Li, Global spread of carbapenem—resistant Enterobacteriaceae: epidemiological features, resistance mechanisms, detection and therapy , Microbiol. Res. 266 (2023) 127249.

[7] P. Nikolic, P. Mudgil, The cell wall, cell membrane and virulence factors of Staphylococcus aureus and their role in antibiotic resistance , Microorganisms 11 (2023).

[8] C.R. MacNair, E.D. Brown, Outer membrane disruption overcomes intrinsic, acquired, and spontaneous antibiotic resistance, mBio 11 (2020).

[9] Z. Hou, L. Liu, J. Wei, B. Xu, Progress in the prevalence, classification and drug resistance mechanisms of methicillin—resistant Staphylococcus aureus , Infect. Drug Resist. 16 (2023) 3271-3292.

[10] S. Sharma, V. Kaushik, M. Kulshrestha, V. Tiwari, Different efflux pump systems in Acinetobacter baumannii and their role in multidrug resistance , Adv. Exp. Med. Biol. 1370 (2023) 155-168.

[11] X.—Z. Li, Multidrug resistance efflux pumps of Pseudomonas aeruginosa: a 10—year update , Chin. J. Antibiotics 37 (2012) 481-500.

[12] C.Y. Xiao, J.E. Lan, X. Liu, Z.L. Sun, X.J. Li, Y.H. Yin, S. Gibbons, Q. Mu, Acetylenic spiroketal enol ethers from Artemisia rupestris and their synergistic antibacterial effects on methicillin—resistant Staphylococcus aureus , Nat. Prod. Res. 38 (2024) 589-593.

[13] Y. Zhou, T. Wang, Y. Guo, S. Liu, J. Wang, Y. Shen, S. Tang, Y. Wang, X. Deng, In Vitro/vivo activity of potential MCR—1 inhibitor in combination with Colistin againsts mcr—1—positive Klebsiella pneumonia , Front. Microbiol. 9 (2018) 1615.

[14] C. de la Fuente—Nunez, F. Reffuveille, L. Fernandez, R.E. Hancock, Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies, Curr. Opin. Microbiol. 16 (2013) 580-589.

[15] C.S.C. Chong, Y.Y. Lau, P.A.M. Michels, C.S.Y. Lim, Insights into biofilm—mediated mechanisms driving last—resort antibiotic resistance in clinical ESKAPE pathogens, Crit. Rev. Microbiol. (2025) 1-26.

[16] C. de la Fuente—Nunez, A. Cesaro, R.E.W. Hancock, Antibiotic failure: beyond antimicrobial resistance, Drug Resist. Updat. 71 (2023) 101012.

[17] N. Hoiby, O. Ciofu, H.K. Johansen, Z.J. Song, C. Moser, P.O. Jensen, S. Molin, M. Givskov, T. Tolker—Nielsen, T. Bjarnsholt, The clinical impact of bacterial biofilms, Int. J. Oral Sci. 3 (2011) 55-65.

[18] J. Ye, X. Chen, Current promising strategies against antibiotic—resistant bacterial infections, Antibiotics (Basel) 12 (2022).

[19] G.A. Durand, D. Raoult, G. Dubourg, Antibiotic discovery: history, methods and perspectives, Int. J. Antimicrob. Agents 53 (2019) 371-382.

[20] H. Zazo, C.I. Colino, J.M. Lanao, Current applications of nanoparticles in infectious diseases, J. Control Release 224 (2016) 86-102.

[21] F. Lotfpour, S. Shahi, A. Farjami, S. Salatin, M. Mahmoudian, S.M. Dizaj, Safety and toxicity issues of therapeutically used nanoparticles from the oral route, Biomed. Res. Int. 2021 (2021) 9322282.

[22] B.G. Cruz, H.S. Dos Santos, P.N. Bandeira, T.H.S. Rodrigues, M.G.C. Matos, M.F. Nascimento, G.G.C. de Carvalho, R. Braz—Filho, A.M.R. Teixeira, S.R. Tintino, H.D.M. Coutinho, Evaluation of antibacterial and enhancement of antibiotic action by the flavonoid kaempferol 7—O—beta—D—(6''—O—cumaroyl)—glucopyranoside isolated from Croton piauhiensis mull , Microb. Pathog. 143 (2020) 104144.

[23] D.L. Paterson, R.A. Bonomo, Extended—spectrum beta—lactamases: a clinical update, Clin. Microbiol. Rev. 18 (2005) 657-686.

[24] S.S. Jean, D. Harnod, P.R. Hsueh, Global threat of carbapenem—resistant gram—negative bacteria, Front. Cell Infect. Microbiol. 12 (2022) 823684.

[25] Z.H. Cui, W.N. Ni, T. Tang, B. He, Z.X. Zhong, L.X. Fang, L. Chen, C. Chen, C.Y. Cui, Y.H. Liu, X.P. Liao, J. Sun, Rapid detection of plasmid—mediated high—level tigecycline resistance in Escherichia coli and Acinetobacter spp , J. Antimicrob. Chemother. 75 (2020) 1479-1483.

[26] Q. Ma, G. Wang, N. Li, X. Wang, X. Kang, Y. Mao, G. Wang, Insights into the effects and mechanism of andrographolide—mediated recovery of susceptibility of methicillin—resistant Staphylococcus aureus to β—lactam antibiotics , Microbiol. Spectr. 11 (2023) e0297822.

[27] G. Eumkeb, S. Sakdarat, S. Siriwong, Reversing beta—lactam antibiotic resistance of Staphylococcus aureus with galangin from Alpinia officinarum Hance and synergism with ceftazidime , Phytomedicine 18 (2010) 40-45.

[28] M. Gallique, K. Wei, V.B. Maisuria, M. Okshevsky, G. McKay, D. Nguyen, N. Tufenkji, Cranberry—derived proanthocyanidins potentiate beta—lactam antibiotics against resistant bacteria, Appl. Environ. Microbiol. 87 (2021).

[29] Z. Teng, Y. Guo, X. Liu, J. Zhang, X. Niu, Q. Yu, X. Deng, J. Wang, Theaflavin—3,3—digallate increases the antibacterial activity of beta—lactam antibiotics by inhibiting metallo—beta—lactamase activity, J. Cell Mol. Med. 23 (2019) 6955-6964.

[30] L. Dhara, A. Tripathi, The use of eugenol in combination with cefotaxime and ciprofloxacin to combat ESBL—producing quinolone—resistant pathogenic Enterobacteriaceae , J. Appl. Microbiol. 129 (2020) 1566-1576.

[31] Y. Zhou, X. Lv, M. Chen, Y. Guo, R. Ding, B. Liu, X. Deng, J. Wang, Characterization of corosolic acid as a KPC—2 inhibitor that increases the susceptibility of KPC—2—positive bacteria to carbapenems, Front. Pharmacol. 11 (2020) 1047.

[32] Y. Zhou, Y. Guo, X. Sun, R. Ding, Y. Wang, X. Niu, J. Wang, X. Deng, Application of oleanolic acid and its analogues in combating pathogenic bacteria In vitro/vivo by a two—pronged strategy of beta—lactamases and hemolysins, ACS. Omega 5 (2020) 11424-11438.

[33] S. Liu, J. Zhang, Y. Zhou, N. Hu, J. Li, Y. Wang, X. Niu, X. Deng, J. Wang, Pterostilbene restores carbapenem susceptibility in New Delhi metallo—beta—lactamase—producing isolates by inhibiting the activity of New Delhi metallo—beta—lactamases, Br. J. Pharmacol. 176 (2019) 4548-4557.

[34] B.M. Benin, T. Hillyer, A.S. Crugnale, A. Fulk, C.A. Thomas, M.W. Crowder, M.A. Smith, W.S. Shin, Taxifolin as a metallo—beta—lactamase inhibitor in combination with Augmentin against Verona imipenemase 2 expressing Pseudomonas aeruginosa , Microorganisms 11 (2023).

[35] L. Xu, Y. Zhou, S. Niu, Z. Liu, Y. Zou, Y. Yang, H. Feng, D. Liu, X. Niu, X. Deng, Y. Wang, J. Wang, A novel inhibitor of monooxygenase reversed the activity of tetracyclines against tet(X3)/tet(X4)—positive bacteria, EBioMedicine 78 (2022) 103943.

[36] A. Vasudevan, D.K. Kesavan, L. Wu, Z. Su, S. Wang, M.K. Ramasamy, W. Hopper, H. Xu, In Silico and In vitro screening of natural compounds as broad—spectrum beta—lactamase inhibitors against Acinetobacter baumannii New Delhi metallo—beta—lactamase—1 (NDM—1) , Biomed. Res. Int. 2022 (2022) 4230788.

[37] T.T. Tran, W.R. Miller, Y. Shamoo, C.A. Arias, Targeting cell membrane adaptation as a novel antimicrobial strategy, Curr. Opin. Microbiol. 33 (2016) 91-96.

[38] I.O. Ayamuang, Y. Teethaisong, K. Sirichaiwetchakoon, S. Suknasang, S. Watthana, Y. Chaiseha, G. Eumkeb, Galangin synergistically revives the antibacterial activity of vancomycin against vancomycin—resistant Enterococcus faecium , J. Appl. Microbiol. 136 (2025).

[39] F. Rodrigues—Costa, J. Slivinski, L.P. Ioca, A.F. Bertonha, R. de Felicio, M.G.D. Cunha, P.V. da Mata Madeira, A.C.G. Cauz, D.M. Trindade, V.F. Freire, C.D. Ropke, A. Gales, M. Brocchi, A.G. Ferreira, F. Gueiros—Filho, D.B.B. Trivella, R.G.S. Berlinck, A. Dessen, Merulinic acid C overcomes gentamicin resistance in Enterococcus faecium , Bioorg. Chem. 100 (2020) 103921.

[40] R. Iseppi, C. Condo, P. Messi, Synergistic inhibition of methicillin—resistant Staphylococcus aureus (MRSA) by Melaleuca alternifolia Chell (Tea Tree) and eucalyptus globulus Labill. Essential oils in association with oxacillin , Antibiotics. (Basel) 12 (2023).

[41] K. Akilandeswari, K. Ruckmani, Synergistic antibacterial effect of apigenin with β—lactam antibiotics and modulation of bacterial resistance by a possible membrane effect against methicillin resistant Staphylococcus aureus , Cell. Mol. Biol. (Noisy—le—grand) 62 (2016) 74-82.

[42] S. Farooq, A.T. Wahab, C.D. Fozing, A.U. Rahman, M.I. Choudhary, Artonin I inhibits multidrug resistance in Staphylococcus aureus and potentiates the action of inactive antibiotics in vitro , J. Appl. Microbiol. 117 (2014) 996-1011.

[43] P. Aelenei, C.M. Rimbu, C.E. Horhogea, A. Lobiuc, A.N. Neagu, S.I. Dunca, I. Motrescu, G. Dimitriu, A.C. Aprotosoaie, A. Miron, Prenylated phenolics as promising candidates for combination antibacterial therapy: morusin and kuwanon G, Saudi. Pharm. J. 28 (2020) 1172-1181.

[44] G. Celenza, B. Segatore, D. Setacci, P. Bellio, F. Brisdelli, M. Piovano, J.A. Garbarino, M. Nicoletti, M. Perilli, G. Amicosante, In vitro antimicrobial activity of pannarin alone and in combination with antibiotics against methicillin—resistant Staphylococcus aureus clinical isolates , Phytomedicine 19 (2012) 596-602.

[45] S.H. Mun, S.B. Kim, R. Kong, J.G. Choi, Y.C. Kim, D.W. Shin, O.H. Kang, D.Y. Kwon, Curcumin reverse methicillin resistance in Staphylococcus aureus , Molecules 19 (2014) 18283-18295.

[46] W.H. Zhao, Z.Q. Hu, S. Okubo, Y. Hara, T. Shimamura, Mechanism of synergy between epigallocatechin gallate and beta—lactams against methicillin—resistant Staphylococcus aureus , Antimicrob. Agents Chemother. 45 (2001) 1737-1742.

[47] S. Abass, S. Zahiruddin, A. Ali, M. Irfan, B. Jan, Q.M.R. Haq, S.A. Husain, S. Ahmad, Development of synergy—based combination of methanolic extract of andrographis paniculata and berberis aristata against E. coli and S. aureus , Curr. Microbiol. 79 (2022) 223.

[48] G. Eumkeb, S. Siriwong, K. Thumanu, Synergistic activity of luteolin and amoxicillin combination against amoxicillin—resistant Escherichia coli and mode of action , J. Photochem. Photobiol. B 117 (2012) 247-253.

[49] G. Eumkeb, S. Siriwong, S. Phitaktim, N. Rojtinnakorn, S. Sakdarat, Synergistic activity and mode of action of flavonoids isolated from smaller galangal and amoxicillin combinations against amoxicillin—resistant Escherichia coli , J. Appl. Microbiol. 112 (2012) 55-64.

[50] C. Qin, N. Tang, Y. Gan, H. Zhao, Y. Li, G.B. Tian, Y.Y. Yang, P. Yuan, X. Ding, Liposomes Co—delivering curcumin and colistin to overcome colistin resistance in bacterial infections, Adv. Healthc. Mater. 12 (2023) e2202903.

[51] G. Singh, M. Katoch, Antimicrobial activities and mechanism of action of Cymbopogon khasianus (Munro ex Hackel) Bor essential oil , BMC. Complement. Med. Ther. 20 (2020) 331.

[52] M. Ginovyan, A. Babayan, A. Shirvanyan, A. Minasyan, M. Qocharyan, B. Kusznierewicz, I. Koss—Mikolajczyk, N. Avtandilyan, A. Vejux, A. Bartoszek, N. Sahakyan, The action mechanisms, anti—cancer and antibiotic—modulation potential of Vaccinium myrtillus L. Extract , Discov. Med. 35 (2023) 590-611.

[53] B. Shin, W. Park, Synergistic effect of Oleanolic acid on aminoglycoside antibiotics against Acinetobacter baumannii , PLoS One 10 (2015) e0137751.

[54] C. Valcourt, P. Saulnier, A. Umerska, M.P. Zanelli, A. Montagu, E. Rossines, M.L. Joly—Guillou, Synergistic interactions between doxycycline and terpenic components of essential oils encapsulated within lipid nanocapsules against gram negative bacteria, Int. J. Pharm. 498 (2016) 23-31.

[55] M. Kang, W. Kim, J. Lee, H.S. Jung, C.O. Jeon, W. Park, 6—Bromo—2—naphthol from Silene armeria extract sensitizes Acinetobacter baumannii strains to polymyxin , Sci. Rep. 12 (2022) 8546.

[56] M. Chitsaz, M.H. Brown, The role played by drug efflux pumps in bacterial multidrug resistance, Essays Biochem. 61 (2017) 127-139.

[57] G. Kumar, A.Kiran Tudu, Tackling multidrug—resistant Staphylococcus aureus by natural products and their analogues acting as NorA efflux pump inhibitors , Bioorg. Med. Chem. 80 (2023) 117187.

[58] K. Singh, R.M. Coopoosamy, N.J. Gumede, S. Sabiu, Computational insights and In vitro validation of antibacterial potential of shikimate pathway—derived phenolic acids as NorA efflux pump inhibitors, Molecules 27 (2022).

[59] H.K. Sharma, P. Gupta, D. Nagpal, M. Mukherjee, V.S. Parmar, V. Lather, Virtual screening and antimicrobial evaluation for identification of natural compounds as the prospective inhibitors of antibacterial drug resistance targets in Staphylococcus aureus , Fitoterapia 168 (2023) 105554.

[60] J. Espinoza, A. Urzua, L. Sanhueza, M. Walter, P. Fincheira, P. Munoz, L. Mendoza, M. Wilkens, Essential oil, extracts, and sesquiterpenes obtained from the heartwood of pilgerodendron uviferum Act as potential inhibitors of the Staphylococcus aureus NorA multidrug efflux pump , Front. Microbiol. 10 (2019) 337.

[61] N.S. Macedo, Z. de Sousa Silveira, P.P.M. Cordeiro, H.D.M. Coutinho, J.P.S. Junior, L.J.Q. Junior, A. Siyadatpanah, B. Kim, F.A.B. da Cunha, M.V. da Silva, Inhibition of Staphylococcus aureus efflux pump by O—eugenol and its toxicity in drosophila melanogaster animal model , Biomed. Res. Int. 2022 (2022) 1440996.

[62] L.M. de Sousa Andrade, A.B.M. de Oliveira, A. Leal, F.A. de Alcantara Oliveira, A.L. Portela, J. de Sousa Lima Neto, J.P. de Siqueira—Junior, G.W. Kaatz, C.Q. da Rocha, H.M. Barreto, Antimicrobial activity and inhibition of the NorA efflux pump of Staphylococcus aureus by extract and isolated compounds from Arrabidaea brachypoda , Microb. Pathog. 140 (2020) 103935.

[63] H. Yu, Y. Wang, X. Wang, J. Guo, H. Wang, H. Zhang, F. Du, Jatrorrhizine suppresses the antimicrobial resistance of methicillin—resistant Staphylococcus aureus , Exp. Ther. Med. 18 (2019) 3715-3722.

[64] C.Y. Xiao, Z.L. Sun, J. Huang, R.S. Li, J.M. He, S. Gibbons, D.W. Ju, Q. Mu, Neolignans from Piper betle have synergistic activity against antibiotic—resistant Staphylococcus aureus , J. Org. Chem. 86 (2021) 11072-11085.

[65] Z.L. Sun, S.C. Sun, J.M. He, J.E. Lan, S. Gibbons, Q. Mu, Synergism of sophoraflavanone G with norfloxacin against effluxing antibiotic—resistant Staphylococcus aureus , Int. J. Antimicrob. Agents 56 (2020) 106098.

[66] S. Hassanzadeh, S. Ganjloo, M.R. Pourmand, R. Mashhadi, K. Ghazvini, Epidemiology of efflux pumps genes mediating resistance among Staphylococcus aureus; A systematic review , Microb. Pathog. 139 (2020) 103850.

[67] J.M. He, S.C. Sun, Z.L. Sun, J.T. Chen, Q. Mu, Isovalerylshikonin, a new resistance—modifying agent from Arnebia euchroma, supresses antimicrobial resistance of drug—resistant Staphylococcus aureus , Int. J. Antimicrob. Agents 53 (2019) 70-73.

[68] P. Ahirrao, R. Tambat, N. Chandal, N. Mahey, A. Kamboj, U.K. Jain, I.P. Singh, S.M. Jachak, H.S. Nandanwar, MsrA efflux pump inhibitory activity of piper cubeba L.f. and its phytoconstituents against Staphylococcus aureus RN4220 , Chem. Biodivers. 17 (2020) e2000144.

[69] A.E. Koshak, H.M. Okairy, M.A. Elfaky, H.M. Abdallah, G.A. Mohamed, S.R.M. Ibrahim, A.A. Alzain, M. Abulfaraj, W.A.H. Hegazy, S.I. Nazeih, Antimicrobial and anti—virulence activities of 4—shogaol from grains of paradise against gram—negative bacteria: integration of experimental and computational methods, J. Ethnopharmacol. 323 (2024) 117611.

[70] J. Kobylka, M.S. Kuth, R.T. Muller, E.R. Geertsma, K.M. Pos, AcrB: a mean, keen, drug efflux machine, Ann. N. Y. Acad. Sci. 1459 (2020) 38-68.

[71] G.R. Dwivedi, A. Maurya, D.K. Yadav, F. Khan, M.P. Darokar, S.K. Srivastava, Drug resistance Reversal potential of ursolic acid derivatives against nalidixic acid— and multidrug—resistant Escherichia coli , Chem. Biol. Drug Des. 86 (2015) 272-283.

[72] L. Dhara, A. Tripathi, Cinnamaldehyde: a compound with antimicrobial and synergistic activity against ESBL—producing quinolone—resistant pathogenic Enterobacteriaceae , Eur. J. Clin. Microbiol. Infect. Dis. 39 (2020) 65-73.

[73] L. Xie, J. Li, Q. Peng, X. Liu, F. Lin, X. Dai, B. Ling, Contribution of RND superfamily multidrug efflux pumps AdeABC, AdeFGH, and AdeIJK to antimicrobial resistance and virulence factors in multidrug—resistant Acinetobacter baumannii AYE , Antimicrob. Agents Chemother. 69 (2025) e0185824.

[74] X. Li, Y. Song, L. Wang, G. Kang, P. Wang, H. Yin, H. Huang, A potential combination therapy of Berberine hydrochloride with antibiotics against multidrug—resistant Acinetobacter baumannii , Front. Cell Infect. Microbiol. 11 (2021) 660431.

[75] F. Ahmadi, B. Khalvati, S. Eslami, M. Mirzaii, N. Roustaei, F. Mazloomirad, S.S. Khorramrooz, The inhibitory effect of Thioridazine on adeB efflux pump gene expression in multidrug—resistant Acinetobacter baumannii isolates using real time PCR , Avicenna J. Med. Biotechnol. 14 (2022) 132-136.

[76] S. Keyhani, M.Y. Alikhani, A. Doosti—Irani, L. Shokoohizadeh, Effect of Mentha longifolia essential oil on oqxA efflux pump gene expression and biofilm formation in ciprofloxacin—resistant Klebsiella pneumoniae strains , Iran. J. Microbiol. 16 (2024) 552-559.

[77] S. Lakhundi, K. Zhang, Methicillin—resistant Staphylococcus aureus: molecular characterization, evolution, and epidemiology , Clin. Microbiol. Rev. 31 (2018).

[78] Q.Q. Li, J. Luo, X.Q. Liu, D.Y. Kwon, O.H. Kang, Eleutheroside K isolated from Acanthopanax henryi (Oliv.) Harms suppresses methicillin resistance of Staphylococcus aureus , Lett. Appl. Microbiol. 72 (2021) 669-676.

[79] S.H. Eom, S.K. Kang, D.S. Lee, J.I. Myeong, J. Lee, H.W. Kim, K.H. Kim, J.Y. Je, W.K. Jung, Y.M. Kim, Synergistic antibacterial effect and antibacterial action mode of chitosan—ferulic acid conjugate against methicillin—resistant Staphylococcus aureus , J. Microbiol. Biotechnol. 26 (2016) 784-789.

[80] C. Santiago, E.L. Pang, K.H. Lim, H.S. Loh, K.N. Ting, Reversal of ampicillin resistance in MRSA via inhibition of penicillin—binding protein 2a by Acalypha wilkesiana , Biomed. Res. Int. 2014 (2014) 965348.

[81] I.C. Materon, T. Palzkill, Structural biology of MCR—1—mediated resistance to polymyxin antibiotics, Curr. Opin. Struct. Biol. 82 (2023) 102647.

[82] Y. Guo, X. Lv, Y. Wang, Y. Zhou, N. Lu, X. Deng, J. Wang, Honokiol restores polymyxin susceptibility to MCR—1—positive pathogens both In vitro and In vivo, Appl. Environ. Microbiol. 86 (2020).

[83] Q. Sheng, N. Wang, Y. Zhou, X. Deng, X. Hou, J. Wang, J. Qiu, Y. Deng, A new function of thymol nanoemulsion for reversing colistin resistance in Salmonella enterica serovar Typhimurium infection , J. Antimicrob. Chemother. 78 (2023) 2983-2994.

[84] L. Karygianni, Z. Ren, H. Koo, T. Thurnheer, Biofilm matrixome: extracellular components in structured microbial communities, Trends. Microbiol. 28 (2020) 668-681.

[85] C.W. Hall, T.F. Mah, Molecular mechanisms of biofilm—based antibiotic resistance and tolerance in pathogenic bacteria, FEMS Microbiol. Rev. 41 (2017) 276-301.

[86] Y. Wang, T. Li, W. Xue, Y. Zheng, Y. Wang, N. Zhang, Y. Zhao, J. Wang, Y. Li, C. Wang, W. Hu, Physicochemical and biological insights into the molecular interactions between extracellular DNA and exopolysaccharides in myxococcus xanthus biofilms , Front. Microbiol. 13 (2022) 861865.

[87] L. Bin, D. McGiffin, T. Nguyen, L. Wang, Y. Sun, L. Ye, M. Han, C. Sheng, T.—H. Lee, M.—I. Aguilar, A.Y. Peleg, Y. Qu, Accurate quantitation of antibiotic penetration through staphylococcal biofilms, Biofilm 10 (2025).

[88] R. Roy, M. Tiwari, G. Donelli, V. Tiwari, Strategies for combating bacterial biofilms: a focus on anti—biofilm agents and their mechanisms of action, Virulence 9 (2018) 522-554.

[89] X. He, W. Zhang, Q. Cao, Y. Li, G. Bao, T. Lin, J. Bao, C. Chang, C. Yang, Y. Yin, J. Xu, Z. Ren, Y. Jin, F. Lu, Global downregulation of penicillin resistance and biofilm formation by MRSA is associated with the interaction between kaempferol rhamnosides and quercetin, Microbiol. Spectr. 10 (2022) e0278222.

[90] R. Roy, P. Paul, P. Chakraborty, M. Malik, S. Das, S. Chatterjee, A. Maity, M. Dasgupta, R.K. Sarker, S. Sarkar, A. Das Gupta, P. Tribedi, Cuminaldehyde and tobramycin forestall the biofilm threats of Staphylococcus aureus: a combinatorial strategy to evade the biofilm challenges , Appl. Biochem. Biotechnol. 196 (2024) 7588-7613.

[91] M.A. Khoshi, S. Keyvani—Ghamsari, K. Khorsandi, Gallic acid synergistically enhances the antibacterial activity of azithromycin in MRSA, Int. Microbiol. (2024).

[92] S. Asadi, B. Nayeri—Fasaei, T. Zahraei—Salehi, R. Yahya—Rayat, N. Shams, A. Sharifi, Antibacterial and anti—biofilm properties of carvacrol alone and in combination with cefixime against Escherichia coli , BMC Microbiol. 23 (2023) 55.

[93] L.Y. Chimi, B.N. Bisso, G.S.S. Njateng, J.P. Dzoyem, Antibiotic—potentiating effect of some bioactive natural products against planktonic cells, biofilms, and virulence factors of Pseudomonas aeruginosa , Biomed. Res. Int. 2023 (2023) 9410609.

[94] H. Liu, H. Chen, Z. Ma, Y. Zhang, S. Zhang, D. Zhao, Z. Yao, T. Zhou, Z. Wang, Plumbagin enhances antimicrobial and anti—biofilm capacities of chlorhexidine against clinical Klebsiella pneumoniae while reducing resistance mutations , Microbiol. Spectr. 12 (2024) e0089624.

[95] H. Wu, C. Moser, H.Z. Wang, N. Høiby, Z.J. Song, Strategies for combating bacterial biofilm infections, Int. J. Oral Sci. 7 (2015) 1-7.

[96] Y. Tan, M. Leonhard, D. Moser, S. Ma, B. Schneider—Stickler, Antibiofilm efficacy of curcumin in combination with 2—aminobenzimidazole against single— and mixed—species biofilms of Candida albicans and Staphylococcus aureus , Colloids. Surf. B Biointerfaces 174 (2019) 28-34.

[97] B. Bisso Ndezo, C.R. Tokam Kuate, J.P. Dzoyem, Synergistic antibiofilm efficacy of Thymol and Piperine in combination with three aminoglycoside antibiotics against Klebsiella pneumoniae biofilms , Can. J. Infect. Dis. Med. Microbiol. 2021 (2021) 7029944.

[98] S. Luo, X. Kang, X. Luo, C. Li, G. Wang, Study on the inhibitory effect of quercetin combined with gentamicin on the formation of Pseudomonas aeruginosa and its bioenvelope , Microb. Pathog. 182 (2023) 106274.

[99] D. Wojnicz, D. Tichaczek—Goska, M. Kicia, Pentacyclic triterpenes combined with ciprofloxacin help to eradicate the biofilm formed in vitro by Escherichia coli , Indian J. Med. Res. 141 (2015) 343-353.

[100] V. Cepas, S.M. Soto, Relationship between virulence and resistance among gram—negative bacteria, Antibiotics (Basel) 9 (2020).

[101] S. Alharthi, S.E. Alavi, P.M. Moyle, Z.M. Ziora, Sortase A (SrtA) inhibitors as an alternative treatment for superbug infections, Drug Discov. Today 26 (2021) 2164-2172.

[102] J. Feng, S. Michalik, A.N. Varming, J.H. Andersen, D. Albrecht, L. Jelsbak, S. Krieger, K. Ohlsen, M. Hecker, U. Gerth, H. Ingmer, D. Frees, Trapping and proteomic identification of cellular substrates of the ClpP protease in Staphylococcus aureus , J. Proteome Res. 12 (2013) 547-558.

[103] W. Song, L. Wang, Y. Zhao, G. Lanzi, X. Wang, C. Zhang, J. Guan, W. Wang, X. Guo, Y. Meng, B. Wang, Y. Zhao, Hibifolin, a natural sortase A inhibitor, attenuates the pathogenicity of Staphylococcus aureus and enhances the antibacterial activity of cefotaxime , Microbiol. Spectr. 10 (2022) e0095022.

[104] W. Jing, D. Guo, Z. Ning, Y. Yang, T. Liu, M. Wang, H. Gao, New polyphenolic glycosides from the stems of caesalpinia cucullata and their inhibitory effect on methicillin—resistant Staphylococcus aureus with different ways , Bioorg. Chem. 129 (2022) 106193.

[105] W. Song, L. Wang, M. Jin, X. Guo, X. Wang, J. Guan, Y. Zhao, Punicalagin, an inhibitor of sortase A, is a promising therapeutic drug to combat methicillin—resistant Staphylococcus aureus infections , Antimicrob. Agents Chemother. 66 (2022) e0022422.

[106] X. Wang, L. Wei, L. Wang, X. Chen, X. Kong, Y. Luan, J. Guan, X. Guo, Y. Shi, T. Wang, B. Wang, W. Song, Y. Zhao, Scutellarin potentiates vancomycin against lethal pneumonia caused by methicillin—resistant Staphylococcus aureus through dual inhibition of sortase A and caseinolytic peptidase P , Biochem. Pharmacol. 199 (2022) 114982.

[107] X. Kong, B. Wang, X. Chen, L. Wang, X. Wang, J. Hou, L. Wei, L. Sui, C. Zhang, J. Guan, Y. Luan, W. Wang, W. Song, Y. Zhao, Hinokiflavone attenuates the virulence of methicillin—resistant Staphylococcus aureus by targeting caseinolytic protease P , Antimicrob. Agents Chemother. 66 (2022) e0024022.

[108] F. Wang, Q. He, J. Yin, S. Xu, W. Hu, L. Gu, BrlR from Pseudomonas aeruginosa is a receptor for both cyclic di—GMP and pyocyanin , Nat. Commun. 9 (2018) 2563.

[109] N. Mok, S.Y. Chan, S.Y. Liu, S.L. Chua, Vanillin inhibits PqsR—mediated virulence in Pseudomonas aeruginosa , Food Funct. 11 (2020) 6496-6508.

[110] P. Chakraborty, P. Paul, M. Kumari, S. Bhattacharjee, M. Singh, D. Maiti, D.G. Dastidar, Y. Akhter, T. Kundu, A. Das, P. Tribedi, Attenuation of Pseudomonas aeruginosa biofilm by thymoquinone: an individual and combinatorial study with tetrazine— capped silver nanoparticles and tryptophan , Folia Microbiol. (Praha) 66 (2021) 255-271.

[111] B.M. Hariri, D.B. McMahon, B. Chen, N.D. Adappa, J.N. Palmer, D.W. Kennedy, R.J. Lee, Plant flavones enhance antimicrobial activity of respiratory epithelial cell secretions against Pseudomonas aeruginosa , PLoS One 12 (2017) e0185203.

[112] S. Chatterjee, P. Paul, P. Chakraborty, S. Das, A. Das Gupta, R. Roy, M. Malik, S. Sarkar, R.K. Sarker, P. Tribedi, Combinatorial application of cuminaldehyde and gentamicin shows enhanced antimicrobial and antibiofilm action on Pseudomonas aeruginosa , Folia Microbiol. (Praha) (2023).

[113] X. Zeng, Y. Zou, J. Zheng, S. Qiu, L. Liu, C. Wei, Quorum sensing—mediated microbial interactions: mechanisms, applications, challenges and perspectives, Microbiol. Res. 273 (2023) 127414.

[114] S.T. Rutherford, B.L. Bassler, Bacterial quorum sensing: its role in virulence and possibilities for its control, Cold. Spring. Harb. Perspect. Med. 2 (2012).

[115] K. Knap, K. Kwiecien, D. Ochonska, K. Reczynska—Kolman, E. Pamula, M. Brzychczy—Wloch, Synergistic effect of antibiotics, alpha—linolenic acid and solvent type against Staphylococcus aureus biofilm formation , Pharmacol. Rep. 76 (2024) 1456-1469.

[116] G. Mitchell, M. Lafrance, S. Boulanger, D.L. Seguin, I. Guay, M. Gattuso, E. Marsault, K. Bouarab, F. Malouin, Tomatidine acts in synergy with aminoglycoside antibiotics against multiresistant Staphylococcus aureus and prevents virulence gene expression , J. Antimicrob. Chemother. 67 (2012) 559-568.

[117] N. Bian, X. Chen, X. Ren, Z. Yu, M. Jin, X. Chen, C. Liu, Y. Luan, L. Wei, Y. Chen, W. Song, Y. Zhao, B. Wang, T. Jiang, C. Zhang, Z. Shu, X. Su, L. Wang, 7,8—Dihydroxyflavone attenuates the virulence of Staphylococcus aureus by inhibiting alpha—hemolysin , World J. Microbiol. Biotechnol. 38 (2022) 200.

[118] Y. Qi, J. Hou, Y. Zhao, W. Song, L. Wang, H. Chen, G. Chen, An inhibitory effect of schisandrone on alpha—hemolysin expression to combat methicillin—resistant staphylococcus aureus infections , World J. Microbiol. Biotechnol. 39 (2022) 3.

[119] D. Kart, T. Recber, E. Nemutlu, M. Sagiroglu, Sub—inhibitory concentrations of ciprofloxacin alone and combinations with plant—derived compounds against P. aeruginosa biofilms and their effects on the metabolomic profile of P. aeruginosa biofilms , Antibiotics (Basel) 10 (2021).

[120] J. Luo, B. Dong, K. Wang, S. Cai, T. Liu, X. Cheng, D. Lei, Y. Chen, Y. Li, J. Kong, Y. Chen, Baicalin inhibits biofilm formation, attenuates the quorum sensing—controlled virulence and enhances Pseudomonas aeruginosa clearance in a mouse peritoneal implant infection model , PLoS One 12 (2017) e0176883.

[121] P.S. Yap, T. Krishnan, B.C. Yiap, C.P. Hu, K.G. Chan, S.H. Lim, Membrane disruption and anti—quorum sensing effects of synergistic interaction between Lavandula angustifolia (lavender oil) in combination with antibiotic against plasmid—conferred multi—drug—resistant Escherichia coli , J. Appl. Microbiol. 116 (2014) 1119-1128.

[122] P.S. Yap, T. Krishnan, K.G. Chan, S.H. Lim, Antibacterial mode of action of cinnamomum verum bark essential oil, alone and in combination with piperacillin, against a multi—drug—resistant Escherichia coli strain , J. Microbiol. Biotechnol. 25 (2015) 1299-1306.

[123] A. Sen, J.A. Imlay, How microbes defend themselves from incoming hydrogen peroxide, Front. Immunol. 12 (2021) 667343.

[124] A. Vaishampayan, E. Grohmann, Antimicrobials functioning through ROS—mediated mechanisms: current insights, Microorganisms 10 (2021).

[125] M. Dryden, Reactive oxygen species: a novel antimicrobial, Int. J. Antimicrob. Agents 51 (2018) 299-303.

[126] Y. Zhao, T. Zhang, Y. Liang, X. Xie, H. Pan, M. Cao, S. Wang, D. Wu, J. Wang, C. Wang, W. Hu, Combination of aloe emodin, emodin, and rhein from Aloe with EDTA sensitizes the resistant Acinetobacter baumannii to polymyxins , Front. Cell Infect. Microbiol. 14 (2024) 1467607.

[127] C. Lu, N. Zhang, S. Kou, L. Gao, B. Peng, Y. Dai, J. Zheng, Sanguinarine synergistically potentiates aminoglycoside—mediated bacterial killing, Microb. Biotechnol. 15 (2022) 2055-2070.

[128] S.B. Zotchev, Unlocking the potential of bacterial endophytes from medicinal plants for drug discovery, Microb. Biotechnol. 17 (2024) e14382.

[129] S. Alfei, A.M. Schito, β—lactam antibiotics and β—lactamase enzymes inhibitors, part 2: our limited resources, Pharmaceuticals (Basel) 15 (2022).

[130] R.J. Lambert, P.N. Skandamis, P.J. Coote, G.J. Nychas, A study of the minimum inhibitory concentration and mode of action of oregano essential oil, thymol and carvacrol, J. Appl. Microbiol. 91 (2001) 453-462.

[131] T. Jiang, X. Zhu, Z. Yin, R. Gao, Y. Li, C. Li, Q. Meng, X. Zhu, W. Song, X. Su, Dual role of Baimao—Longdan—Congrong—Fang in inhibiting Staphylococcus aureus virulence factors and regulating TNF—α/TNFR1/NF—κb/MMP9 axis , Phytomedicine 139 (2025) 156477.