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

Cell Rep. 2016 Jan 26;14(3):572-585. doi: 10.1016/j.celrep.2015.12.056. Epub 2016 Jan 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antioxidants / analysis
  • Antioxidants / metabolism*
  • Antitubercular Agents / pharmacology
  • Bacterial Proteins / metabolism
  • Carbon / metabolism
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Cysteine / metabolism
  • Disease Susceptibility
  • Energy Metabolism / physiology*
  • Ergothioneine / analysis
  • Ergothioneine / metabolism*
  • Glycopeptides / metabolism
  • Inositol / metabolism
  • Lung / microbiology
  • Lung / pathology
  • Macrophages / microbiology
  • Mice
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / metabolism
  • Mycobacterium tuberculosis / pathogenicity*
  • Oxidation-Reduction
  • Principal Component Analysis
  • Tandem Mass Spectrometry
  • Transcription Factors / metabolism
  • Virulence*

Substances

  • Antioxidants
  • Antitubercular Agents
  • Bacterial Proteins
  • Glycopeptides
  • Transcription Factors
  • mycothiol
  • Inositol
  • Carbon
  • Ergothioneine
  • Cysteine