1. Facile metabolic reprogramming distinguishes mycobacterial adaptation to hypoxia and starvation: ketosis drives starvation-induced persistence in M. bovis BCG.
- Author
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Davis NK, Chionh YH, McBee ME, Hia F, Ma D, Cui L, Sharaf ML, Cai WM, Jumpathong W, Levine SS, Alonso S, and Dedon PC
- Subjects
- Glycolysis, Metabolic Reprogramming, Mycobacterium bovis metabolism, Adaptation, Physiological
- Abstract
Mycobacteria adapt to infection stresses by entering a reversible non-replicating persistence (NRP) with slow or no cell growth and broad antimicrobial tolerance. Hypoxia and nutrient deprivation are two well-studied stresses commonly used to model the NRP, yet little is known about the molecular differences in mycobacterial adaptation to these distinct stresses that lead to a comparable NRP phenotype. Here we performed a multisystem interrogation of the Mycobacterium bovis BCG (BCG) starvation response, which revealed a coordinated metabolic shift away from the glycolysis of nutrient-replete growth to depletion of lipid stores, lipolysis, and fatty acid ß-oxidation in NRP. This contrasts with BCG's NRP hypoxia response involving a shift to cholesterol metabolism and triglyceride storage. Our analysis reveals cryptic metabolic vulnerabilities of the starvation-induced NRP state, such as their newfound hypersensitivity to H
2 O2 . These observations pave the way for developing precision therapeutics against these otherwise drug refractory pathogens., (© 2024. The Author(s).)- Published
- 2024
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