Ergothioneine maintains redox and bioenergetic homeostasis essential for drug susceptibility and virulence of Mycobacterium tuberculosis
| Autor: | Loni Guidry, James H. Mazorodze, John H. Adamson, Kyu Y. Rhee, Bridgette M. Cumming, Joel N. Glasgow, Anaximandro Gómez-Velasco, Yossef Av-Gay, Hyungjin Eoh, Horacio Bach, Vineel P. Reddy, Vikram Saini, Krishna C. Chinta, Dirk A. Lamprecht, Melissa Richard-Greenblatt, Adrie J. C. Steyn |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Bioenergetics 030106 microbiology Antitubercular Agents Virulence chemical and pharmacologic phenomena Biology General Biochemistry Genetics and Molecular Biology Article Antioxidants Cell Line Transcriptome Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Mice Bacterial Proteins Tandem Mass Spectrometry Animals Cysteine lcsh:QH301-705.5 Transcription factor Lung Chromatography High Pressure Liquid Principal Component Analysis Macrophages Glycopeptides Ergothioneine respiratory system biology.organism_classification bacterial infections and mycoses Carbon 3. Good health Mycothiol lcsh:Biology (General) Biochemistry chemistry Disease Susceptibility Energy Metabolism Oxidation-Reduction Homeostasis Inositol Transcription Factors |
| Zdroj: | Cell Reports, Vol 14, Iss 3, Pp 572-585 (2016) |
| Popis: | SummaryThe 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|