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Cell Rep. 2016 Jan 26;14(3):572-85. doi: 10.1016/j.celrep.2015.12.056. Epub 2016 Jan 7.

Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis.

Author information

  • 1Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Centers for AIDS Research and Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 2KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa.
  • 3Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 4Department of Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
  • 5Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 6Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Centers for AIDS Research and Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa; Department of Pathology, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban 4001, South Africa. Electronic address: asteyn@uab.edu.

Abstract

The mechanisms by which Mycobacterium tuberculosis (Mtb) maintains metabolic equilibrium to survive during infection and upon exposure to antimycobacterial drugs are poorly characterized. Ergothioneine (EGT) and mycothiol (MSH) are the major redox buffers present in Mtb, but the contribution of EGT to Mtb redox homeostasis and virulence remains unknown. We report that Mtb WhiB3, a 4Fe-4S redox sensor protein, regulates EGT production and maintains bioenergetic homeostasis. We show that central carbon metabolism and lipid precursors regulate EGT production and that EGT modulates drug sensitivity. Notably, EGT and MSH are both essential for redox and bioenergetic homeostasis. Transcriptomic analyses of EGT and MSH mutants indicate overlapping but distinct functions of EGT and MSH. Last, we show that EGT is critical for Mtb survival in both macrophages and mice. This study has uncovered a dynamic balance between Mtb redox and bioenergetic homeostasis, which critically influences Mtb drug susceptibility and pathogenicity.

PMID:
26774486
PMCID:
PMC4732560
DOI:
10.1016/j.celrep.2015.12.056
[PubMed - indexed for MEDLINE]
Free PMC Article
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