Antioxidant adjuvants as a strategy to combat multidrug-resistant gram-negative bacteria: mechanistic insights and translational perspectives

Abstract

Abstract Background Antimicrobial resistance (AMR) is a major global health threat. Multidrug-resistant (MDR) Gram-negative pathogens—including Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii —pose serious therapeutic challenges in both hospital and community settings. These organisms possess diverse resistance mechanisms such as reduced outer membrane permeability, efflux pump overexpression, biofilm formation, enzymatic drug inactivation, and horizontal gene transfer. The global spread of mobile resistance determinants, including mcr genes and carbapenemases, has compromised the efficacy of last-resort antibiotics such as colistin and carbapenems, highlighting the need for alternative therapeutic strategies. Main body Given the limited development of new antibiotics, antioxidant-based non-antibiotic adjuvants have emerged as a promising strategy to restore antimicrobial activity. Bioactive compounds—including flavonoids, polyphenols, melatonin, vitamins, and thiol-containing molecules—exert multiple effects on bacterial physiology. These include disruption of membrane integrity, inhibition of efflux pumps, modulation of redox homeostasis, interference with quorum sensing, and suppression of biofilm formation. Some antioxidants also display host-directed immunomodulatory effects that may reduce inflammation and oxidative tissue injury during infection. Recent preclinical studies (2020–2025) demonstrate synergistic activity between antioxidant adjuvants and conventional antibiotics such as colistin, carbapenems, aminoglycosides, and fluoroquinolones. These combinations can reduce minimum inhibitory concentrations, enhance bacterial killing, and restore antibiotic susceptibility in resistant strains. However, clinical translation remains limited due to challenges including pharmacokinetic variability, uncertain dose optimization, potential drug interactions, and the lack of well-designed clinical trials. Conclusion Antioxidant adjuvants represent a mechanistically diverse strategy for combating MDR Gram-negative infections and restoring antibiotic efficacy. Future progress will require rigorous pharmacokinetic and pharmacodynamic evaluation, standardized synergy testing, and well-designed clinical trials to confirm safety, efficacy, and clinical applicability.