Title | Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Saini V, Cumming BM, Guidry L, Lamprecht DA, Adamson JH, Reddy VP, Chinta KC, Mazorodze JH, Glasgow JN, Richard-Greenblatt M, Gomez-Velasco A, Bach H, Av-Gay Y, Eoh H, Rhee K, Steyn AJC |
Journal | Cell Rep |
Volume | 14 |
Issue | 3 |
Pagination | 572-585 |
Date Published | 2016 Jan 26 |
ISSN | 2211-1247 |
Keywords | Animals, Antioxidants, Antitubercular Agents, Bacterial Proteins, Carbon, Cell Line, Chromatography, High Pressure Liquid, Cysteine, Disease Susceptibility, Energy Metabolism, Ergothioneine, Glycopeptides, Inositol, Lung, Macrophages, Mice, Mycobacterium tuberculosis, Oxidation-Reduction, Principal Component Analysis, Tandem Mass Spectrometry, Transcription Factors, Virulence |
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. |
DOI | 10.1016/j.celrep.2015.12.056 |
Alternate Journal | Cell Rep |
PubMed ID | 26774486 |
PubMed Central ID | PMC4732560 |
Grant List | R56 AI058131 / AI / NIAID NIH HHS / United States R01 AI076389 / AI / NIAID NIH HHS / United States AI058131 / AI / NIAID NIH HHS / United States AI076389 / AI / NIAID NIH HHS / United States R01 AI058131 / AI / NIAID NIH HHS / United States |