Effective Abatement of Multidrug-resistant Pathogens Employing Natural Polyphenols and Polyphenol-based Formulations: A Systematic Review and Integrated Network Pharmacology Approach.

The upsurge in multidrug-resistant (MDR) bacterial pathogens poses a dire global public health concern, limiting the effectiveness of conventional antibiotics. Natural polyphenols and their derivatives have attracted immense attention due to their versatile pharmacological potentials encompassing antimicrobial, anti-biofilm, and anti-quorum sensing activities. However, a comprehensive understanding of polyphenols combating MDR pathogens and the mechanistic interactions needs to be elucidated. This systematic review aimed to evaluate the effectiveness of natural polyphenols and polyphenol-based formulations against MDR bacterial pathogens, along with inherent molecular targets, using an integrated network pharmacology approach. A systematic literature search following PRISMA guidelines was conducted across PubMed, Google Scholar, and the Cochrane databases, including peer-reviewed publications from 2015 to 2025. Studies reporting polyphenolic compounds and derivatives against MDR bacteria were derived based on predefined inclusion and exclusion criteria. Seventeen studies (n = 17), including one clinical trial, met the inclusion criteria solely on polyphenolic compounds against MDR bacteria. Evidence indicates that natural polyphenols and their derivatives exert antimicrobial effects through multiple mechanisms, including efflux pump inhibition, quorum-sensing interference, biofilm disruption, and membrane damage. Further, nanoformulated polyphenols and metal-polyphenol complexes demonstrated enhanced stability, bioavailability, and synergistic activity with antibiotics for combating MDR pathogens. Network pharmacology analysis revealed significant interactions between polyphenols and virulence-related genes in Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, highlighting their potential as multi-target anti-virulence agents. Thus, multi-target mechanisms, combined with antibiotic adjuvant potentials and nanodelivery approaches, envisage future translational research, clinical validation, and sustainable AMR therapies that align with global One Health initiatives and SDG 3.