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Facile metabolic reprogramming distinguishes mycobacterial adaptation to hypoxia and starvation: The role of ketosis in starvation-induced persistence

ABSTRACT: Mycobacteria have the ability to adapt to stressful infection conditions by entering a reversible state of non-replicating persistence (NRP) characterized by slow or no cell growth and increased tolerance to various antimicrobial agents. While hypoxia and nutrient deprivation are commonly used to study this NRP state, there is limited understanding of the molecular distinctions in how mycobacteria adapt to these different stresses to achieve a similar NRP outcome. In this study, we conducted a comprehensive analysis of Mycobacterium bovis BCG's response to starvation, shedding light on a coordinated metabolic shift away from glycolysis during nutrient-rich growth to the depletion of lipid stores, lipolysis, and fatty acid ß-oxidation during NRP. Interestingly, this response differs from BCG's NRP state under hypoxia, where it shifts towards cholesterol metabolism and triglyceride storage. Our investigation also unveiled hidden metabolic vulnerabilities in the NRP state induced by starvation, notably an increased sensitivity to H2O2. These findings open up possibilities for the development of precise therapeutic approaches against these otherwise challenging-to-treat pathogens.

INSTRUMENT(S): LTQ Orbitrap, 6520 Quadrupole Time-of-Flight LC/MS

ORGANISM(S): Mycobacterium Bovis Bcg Str. Pasteur 1173p2

SUBMITTER: Fabian Hia

LAB HEAD: Peter Dedon

PROVIDER: PXD046804 | Pride | 2023-11-09

REPOSITORIES: Pride

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