Proteostasis-targeted antibacterial strategies.

Protein quality control systems are increasingly recognized as a critical determinant of bacterial survival and antibiotic tolerance. Conventional antibiotics predominantly target nucleic acids, protein synthesis, or cell wall synthesis, yet bacterial adaptation and resistance emergence remain major challenges. Targeting the bacterial protein quality control machineries including molecular chaperones and proteases offers a promising strategy to overcome these limitations. Recent advances include small molecules and adaptor/degron mimetics that modulate the activities of chaperones and proteases, aggregation-prone peptides (APPs) that induce proteotoxic stress, and bacterial PROTAC (BacPROTAC) strategies that redirect endogenous proteases. Notably, persister and viable-but-non-culturable (VBNC) cells, which tolerate conventional antibiotics, remain susceptible to proteostasis-targeted approaches, thereby enabling killing in both actively dividing and dormant populations. Furthermore, synergistic strategies combining chaperone inhibition or protease activation with conventional antibiotics enhance bactericidal efficacy, suggesting a potential avenue to mitigate antimicrobial resistance. This review summarizes the mechanistic basis, recent developments, and translational potential of proteostasis-centered antibacterial strategies.