The molecular pathways of polyphenols in combating multidrug-resistant microbial superbugs: a comprehensive mechanistic review

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Background Multidrug-resistant (MDR) bacterial pathogens continue to severely compromise the therapeutic dynamics of modern medicine, placing a severe burden on healthcare systems worldwide. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa , and Enterobacter species are at the frontline of this crisis and are developing resistance mechanisms at an alarming rate. Moreover, the clinical challenge is further complicated by emergent antifungal resistance in Candida auris and Aspergillus fumigatus . In light of a declining antibiotic pipeline, plant-derived polyphenols have again attracted renewed scientific interest because of their multitarget antimicrobial activity. Study synthesis This review summarises evidence in peer-reviewed literature (PubMed, Scopus, Web of Science; 2013–2025) to provide a comprehensive mechanistic analysis of the mechanisms by which polyphenols disrupt MDR pathogens. The mechanisms considered include direct disruption of the bacterial cell envelope with species-specific modalities in Gram-positive versus Gram-negative organisms; inhibition of essential intracellular targets comprising DNA gyrase, fatty acid synthase enzymes (FabI, FabG, FabZ), and the tricarboxylic acid cycle; selective suppression of efflux pump-driven resistance; pro-oxidant ROS generation and metal ion chelation; and quorum sensing interference coupled with multistage antibiofilm activity, as exemplified by polyphenolic compounds, particularly epigallocatechin gallate (EGCG), quercetin, resveratrol, curcumin, and tannic acid, which exert strong antimicrobial and antivirulence effects through interactions with multiple bacterial pathways. Conclusion Regardless of their low bioavailability, rapid first-pass metabolism, and chemical instability challenges, polyphenols present interesting alternatives and adjuvants to traditional antibiotics because of their structural diversity, low host cytotoxicity, and significantly reduced ability to drive resistance selection. Advanced nanoformulation-based delivery systems, structure‒activity relationship-directed semisynthetic optimisation, rigorous standardised in vivo validation models, and the commencement of targeted clinical trials starting with topical applications and combination-adjuvant applications of these natural compounds to unlock the full translational potential of these natural compounds are recommended.

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