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Cell envelope maintenance by PhoP is essential for Mycobacterium tuberculosis methylglyoxal resistance

ABSTRACT: During Mycobacterium tuberculosis infections bacteria are engulfed by macrophages, a main line of defense against invading pathogens. Upon activation, macrophages increase glycolysis producing the antibacterial aldehyde methylglyoxal. To test if bacterial methylglyoxal resistance is required for robust infections, we sought to identify Mycobacterium tuberculosis defense mechanisms against methylglyoxal. We identified phoP mutants were among the most highly sensitive strains to methylglyoxal in vitro. phoP mutants are attenuated in mice but were even more attenuated in mice that accumulate methylglyoxal. We further found phoP bacilli exhibited increased membrane permeability and were more permeable to methylglyoxal. Suppressor mutations in the fatty acid Beta-oxidation genes fadE25 or fixB restored impermeability and resistance to methylglyoxal to a phoP mutant. Together, our data show that a major virulence role for PhoP is to provide Mycobacterium tuberculosis resistance to methylglyoxal toxicity in vivo by regulating cell envelope integrity. The mass spectrometry files supporting this hypothesis are deposited here.

INSTRUMENT(S): timsTOF HT

ORGANISM(S): Mycobacterium Tuberculosis H37rv (ncbitaxon:83332)

SUBMITTER: Beatrix Ueberheide

PROVIDER: MSV000098760 | MassIVE | Thu Aug 07 09:13:00 BST 2025

REPOSITORIES: MassIVE

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