Journal
CELL REPORTS
Volume 14, Issue 3, Pages 572-585Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.12.056
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Funding
- NIH [AI076389, AI058131]
- DOD Discovery Award [PR121320]
- UAB Centers for AIDS Research and Free Radical Biology
- UAB School of Medicine Infectious Diseases
- Global Health and Vaccines Initiative
- Senior Research Training Fellowship from the American Lung Association [RT-232840-N]
- South African Medical Research Council
- Victor Daitz Information Gateway
- Victor Daitz Foundation
- University of KwaZulu-Natal
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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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