Metabolic conservation by protein quality control in Campylobacter jejuni underlies the antibiotic tolerance

Antibiotic tolerance in bacteria emerges as a phenotypic variant known as persisters and has been implicated in recurrent bacterial infections. This tolerance manifests as suppressed metabolism. We demonstrate that Campylobacter jejuni readily forms persisters in response to both ampicillin and ciprofloxacin. Persisters induced by these two antibiotics with different mechanisms of actions experience consistent metabolic reprogramming, characterized by suppressed respiration and energy metabolism while conserving core metabolic processes. We reveal that the coordination of protein homeostasis underlies the metabolic reprogramming involved in persister formation. Mutating the caseinolytic protease gene clpP, a major component of the protein quality control system, compromises persister formation in vitro and impairs bacterial colonization in mouse. However, the deletion of lon, another component of the protein quality control system, or pre-activation of clpP by expressing artificial disordered protein fragments does not affect the antibiotic tolerance. This suggests that specific targets of ClpP rather than the entire quality control system are critical for persister formation. Our results reveal a convergent metabolic reprogramming in persisters, highlighting the potential to limit the emergence of antibiotic tolerance by counteracting adaptive metabolism elicited by antibiotic treatment.