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

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          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.

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          Author and article information

          Journal
          Cell Rep
          Cell reports
          Elsevier BV
          2211-1247
          Jan 26 2016
          : 14
          : 3
          Affiliations
          [1 ] Department 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.
          [2 ] KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa.
          [3 ] Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
          [4 ] Department of Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
          [5 ] Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
          [6 ] Department 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.
          Article
          S2211-1247(15)01497-7 NIHMS747292
          10.1016/j.celrep.2015.12.056
          4732560
          26774486
          3b8b545a-b776-44ea-8414-4c8415932739
          History

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