Bacterial persisters: from mechanism modules to target prioritization and inhibitor development

Persisters constitute a dormant subpopulation within bacterial communities. Upon antibiotic exposure, they survive environmental stress through reversible metabolic stasis, which can lead to persistent and recurrent infections that pose serious threats to public health. Growing evidence indicates that conventional antibiotic treatments fail to eradicate persisters, creating an urgent need to develop persister-targeting inhibitors. However, their development is hindered by the complexity of persister formation mechanisms and the low abundance of persister cells. This paper systematically reviews the mechanisms underlying persister formation. We then propose a target-prioritization framework and an evidence-grading scheme to distinguish exploratory hits from candidates with translational potential. Finally, we discuss strategic approaches and highlight the experimental platforms required for robust validation. This work aims to guide rational target selection and the development of therapeutic strategies and dosing regimens that reduce relapse and improve cure rates.