title: Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis.
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.
authors.affiliation: 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.
authors.forename: Vikram
authors.initials: V
authors.lastname: Saini
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa.
authors.forename: Bridgette M
authors.initials: BM
authors.lastname: Cumming
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Loni
authors.initials: L
authors.lastname: Guidry
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa.
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Lamprecht
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa.
authors.forename: John H
authors.initials: JH
authors.lastname: Adamson
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Vineel P
authors.initials: VP
authors.lastname: Reddy
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Krishna C
authors.initials: KC
authors.lastname: Chinta
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa.
authors.forename: James H
authors.initials: JH
authors.lastname: Mazorodze
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Glasgow
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Richard-Greenblatt
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Anaximandro
authors.initials: A
authors.lastname: Gomez-Velasco
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Horacio
authors.initials: H
authors.lastname: Bach
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Yossef
authors.initials: Y
authors.lastname: Av-Gay
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Eoh
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kyu
authors.initials: K
authors.lastname: Rhee
authors.affiliation: 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.
authors.forename: Adrie J C
authors.initials: AJC
authors.lastname: Steyn
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000032:analysis / Q000378:metabolism*; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism; D002244:Carbon / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000378:metabolism; D004198:Disease Susceptibility; D004734:Energy Metabolism / Q000502:physiology*; D004880:Ergothioneine / Q000032:analysis / Q000378:metabolism*; D006020:Glycopeptides / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity*; D010084:Oxidation-Reduction; D025341:Principal Component Analysis; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors / Q000378:metabolism; D014774:Virulence
chemical_list: D000975:Antioxidants; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D006020:Glycopeptides; D014157:Transcription Factors; C089265:mycothiol; D007294:Inositol; D002244:Carbon; D004880:Ergothioneine; D003545:Cysteine