Metabolic Rewiring of Bacterial Pathogens in Response to Antibiotic Pressure-A Molecular Perspective

Antibiotic pressure exerts profound effects on bacterial physiology, not limited to classical genetic resistance mechanisms. Increasing evidence highlights the ability of pathogens to undergo metabolic rewiring-an adaptive, reversible reorganization of core metabolic pathways that promotes survival under antimicrobial stress. This review provides a comprehensive analysis of antibiotic-induced metabolic adaptations, encompassing glycolysis, the tricarboxylic acid cycle, fermentation, redox balance, amino acid catabolism, and membrane biosynthesis. We critically examine how diverse antibiotic classes-including β-lactams, aminoglycosides, quinolones, glycopeptides, polymyxins, and antimetabolites-interact with bacterial metabolism to induce tolerance and persistence, often preceding stable resistance mutations. In parallel, we explore the ecological and host-derived signals-such as immunometabolites and quorum sensing-that modulate these metabolic responses. Therapeutically, targeting metabolic pathways offers promising strategies to potentiate antibiotic efficacy, including enzyme inhibition, metabolic adjuvants, and precision-guided therapy based on pathogen metabolic profiling. By framing metabolic plasticity as a dynamic and evolutionarily relevant phenomenon, this review proposes a unifying model linking transient tolerance to stable resistance. Integrating metabolic rewiring into antimicrobial research, clinical diagnostics, and therapeutic design represents a necessary paradigm shift in combating bacterial persistence and resistance.