The SOS Response: A Double-Edged Sword between the Persister and Resister Formation

Antimicrobial agents have revolutionized the treatment of infectious diseases; however, their widespread and extensive use has accelerated the emergence of antimicrobial resistance (AMR). While resistance driven by mutation and gene transfer poses a major threat, the transiently dormant subpopulation, called persisters, poses an equally significant challenge. The bacterial SOS response, triggered by extensive DNA damage, promotes resistance by inducing mutations in the target protein, activating drug efflux systems and horizontally transferring genetic material. Furthermore, SOS has been implicated in controlling toxin-antitoxin modules, as observed in the tisB/istR system in Escherichia coli, which further facilitates the emergence of persister populations. Although persistence and resistance are often studied separately, their shared regulation by the SOS system remains unexplored. Targeting SOS regulators, such as RecA and LexA, and DNA damage responders, including error-prone polymerases, can significantly help control the emergence and spread of AMR, although such approaches are in their early translational stages. This review explores the role of the SOS response as a unifying mechanism linking resistance and persistence, while evaluating emerging therapeutic strategies targeting SOS regulators and associated stress response pathways as antievolution approaches to combat AMR effectively.