Protein quality control modulates the metabolic conservation in antibiotic tolerantCampylobacter jejuni

ABSTRACT Bacterial persistence enables survival during lethal antibiotic exposure and is implicated in recurrent infections, yet the physiology underlying bacterial persistence in many pathogens remains poorly defined. Here we show that exposure of Campylobacter jejuni to ampicillin or ciprofloxacin generates an antibiotic-persistent subpopulation. Rather than undergoing global metabolic shutdown, persister cells adopted a metabolically constrained state characterized by selective maintenance of oxidative phosphorylation and bioenergetic metabolism through coordinated proteostasis control. The ATP-dependent protease ClpP was essential for entry into this persistent state. Loss of ClpP disrupted proteostasis of the electron transport chain, specifically impaired bd-like terminal oxidase integrity, and reduced survival in vivo and in macrophages. These findings identify ClpP-dependent maintenance of redox and bioenergetic homeostasis as critical determinants of C. jejuni persistence and highlight metabolic remodeling as a defining feature of antibiotic tolerance. These insights may inform future therapeutic strategies aimed at disrupting persistence and improving antibiotic efficacy. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵& Food Science Program, Department of Chemistry, Carleton University, Ottawa, Ontario, K1S 5B6, Canada ↵^ Department of Food and Bioproduct Sciences, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5A8, Canada ↵Ω STEMCELL Technologies Ltd, Vancouver, BC V6A 1B6, Canada. In this revised version, we added Seahorse and western blot data, incorporated additional up-to-date findings, and included more phenotypic assays to assess redox balance. We also substantially revised the Discussion and refined the proposed model based on the more complete evidence now included in the manuscript.