Mycobacterium tuberculosis h2s functions as a sink to modulate central metabolism, bioenergetics, and drug susceptibility

Tafara T.R. Kunota, Md Aejazur Rahman, Barry E. Truebody, Jared S. Mackenzie, Vikram Saini, Dirk A. Lamprecht, John H. Adamson, Ritesh R. Sevalkar, Jack R. Lancaster, Michael Berney, Joel N. Glasgow, Adrie J.C. Steyn

Research output: Contribution to journalArticlepeer-review

Abstract

H2S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H2S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H2S and its role in Mtb physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical Mtb strains produce H2S, whereas H2S production in non-pathogenic M. smegmatis is barely detectable. We identified Rv3684 (Cds1) as an H2S-producing enzyme in Mtb and show that cds1 disruption reduces, but does not eliminate, H2S production, suggesting the involvement of multiple genes in H2S production. We identified endogenous H2S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome bd. Importantly, H2S plays a key role in central metabolism by modulating the balance between oxidative phosphorylation and glycolysis, and it functions as a sink to recycle sulfur atoms back to cysteine to maintain sulfur homeostasis. Lastly, Mtb-generated H2S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of Mtb physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics.

Original languageEnglish (US)
Article number1285
JournalAntioxidants
Volume10
Issue number8
DOIs
StatePublished - Aug 2021

Keywords

  • Agilent Seahorse XFe96
  • Bioenergetics
  • Cysteine
  • CytBD
  • Energy metabolism
  • Ergothioneine
  • HS
  • Metabolomics
  • Mycobacterium tuberculosis
  • Mycothiol
  • Redox homeostasis
  • Respiration
  • Rv3684

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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