Bacterial secondary metabolites as resistance-modifying adjuvants: microbial origins, molecular mechanisms, and...

The accelerating crisis of antimicrobial resistance (AMR) necessitates strategies that extend beyond the continual discovery of new conventional antibiotics. Bacterial secondary metabolites, historically valued as sources of antimicrobial scaffolds, are increasingly recognized for their roles as resistance-modifying and anti-virulence agents. This review synthesizes key advances from 2020 to 2025 that reposition bacterial secondary metabolites as integral components of next-phase AMR intervention strategies. We examine their chemical and biosynthetic diversity, ecological functions, and molecular mechanisms of action, including efflux pump inhibition, β-lactamase suppression, interference with ribosomal protection, and disruption of biofilms and quorum-sensing networks. Mechanistic and evolutionary analyses are integrated to explain why many metabolites impose higher barriers to resistance development than single-target antibiotics. We further discuss contemporary discovery and optimization pipelines encompassing genome mining, multi-omics approaches, synthetic biology, and AI-assisted structure-activity modeling. Translational considerations are critically evaluated, with emphasis on pharmacokinetic and pharmacodynamic constraints, rational combination therapy design, preclinical validation, and emerging development pipelines. Regulatory, manufacturing, and commercialization challenges are addressed alongside opportunities enabled by nanocarrier delivery systems, microbiome-informed strategies, and personalized medicine. Overall, this review highlights bacterial secondary metabolites as evolution-resilient anti-resistance modalities capable of restoring and extending the efficacy of existing antibiotics, offering a pragmatic and mechanistically grounded path forward in combating AMR.