Metabolite-driven reprogramming of bacterial persisters: Mechanisms and therapeutic opportunities for overcoming antibiotic tolerance.

Bacterial persisters constitute a heterogeneous subpopulation of dormant or slow-growing cells capable of surviving harsh environmental conditions, including antibiotic exposure. These cells are strongly associated with the failure of clinical antibiotic therapies and the recurrence of chronic bacterial infections. A comprehensive understanding of the physiological features of bacterial persisters is therefore critical for the development of targeted interventions aimed at overcoming the limitations of conventional antibiotic treatments. In this review, we summarize current models of bacterial persister formation, with particular emphasis on the pivotal role of reduced metabolic activity in mediating antibiotic tolerance. We further elucidate the mechanisms through which exogenous metabolites-such as sugars, lipids, and nucleic acid derivatives-induce metabolic reprogramming, thereby reversing multidrug resistance in bacterial persisters. Furthermore, we summarized the major barriers limiting the clinical translation of metabolite-assisted "wake-and-kill" strategies and outlined future prospects for their application. In conclusion, restoring bacterial metabolic activity through targeted metabolite interventions represents a promising avenue to overcome antibiotic tolerance, paving the way for next-generation therapeutic strategies against persistent infections.