دورية أكاديمية
أعرض في EDS

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.

التفاصيل البيبلوغرافية
العنوان: Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.
المؤلفون: Mackenzie JS; Africa Health Research Institute, Durban, 4001, South Africa., Lamprecht DA; Janssen Pharmaceutica, Global Public Health, Turnhoutseweg 30, 2340, Beerse, Belgium., Asmal R; Africa Health Research Institute, Durban, 4001, South Africa., Adamson JH; Africa Health Research Institute, Durban, 4001, South Africa., Borah K; Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK., Beste DJV; Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK., Lee BS; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Pethe K; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore., Rousseau S; Texas A&M University, Department of Biochemistry and Biophysics, College Station, TX, USA., Krieger I; Texas A&M University, Department of Biochemistry and Biophysics, College Station, TX, USA., Sacchettini JC; Texas A&M University, Department of Biochemistry and Biophysics, College Station, TX, USA., Glasgow JN; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA., Steyn AJC; Africa Health Research Institute, Durban, 4001, South Africa. asteyn@uab.edu.; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. asteyn@uab.edu.; Center for AIDS Research and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA. asteyn@uab.edu.
المصدر: Nature communications [Nat Commun] 2020 Nov 30; Vol. 11 (1), pp. 6092. Date of Electronic Publication: 2020 Nov 30.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Anti-Bacterial Agents/*pharmacology , Diarylquinolines/*pharmacology , Glycolysis/*drug effects , Mycobacterium tuberculosis/*drug effects , Mycobacterium tuberculosis/*metabolism, Antitubercular Agents/pharmacology ; Bacterial Proteins/metabolism ; Carbon Cycle/drug effects ; Citric Acid Cycle/drug effects ; Energy Metabolism/drug effects ; Glyoxylates ; Mycobacterium tuberculosis/genetics ; Oxidative Phosphorylation ; Tuberculosis/microbiology
مستخلص: The approval of bedaquiline (BDQ) for the treatment of tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death in Mycobacterium tuberculosis (Mtb). Using 13 C isotopomer analysis, we show that BDQ-treated Mtb redirects central carbon metabolism to induce a metabolically vulnerable state susceptible to genetic disruption of glycolysis and gluconeogenesis. Metabolic flux profiles indicate that BDQ-treated Mtb is dependent on glycolysis for ATP production, operates a bifurcated TCA cycle by increasing flux through the glyoxylate shunt, and requires enzymes of the anaplerotic node and methylcitrate cycle. Targeting oxidative phosphorylation (OXPHOS) with BDQ and simultaneously inhibiting substrate level phosphorylation via genetic disruption of glycolysis leads to rapid sterilization. Our findings provide insight into the metabolic mechanism of BDQ-induced cell death and establish a paradigm for the development of combination therapies that target OXPHOS and glycolysis.
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معلومات مُعتمدة: R01 AI134810 United States AI NIAID NIH HHS; R01 AI137043 United States AI NIAID NIH HHS; MR/K01224X/1 United Kingdom MRC_ Medical Research Council; R01 AI152110 United States AI NIAID NIH HHS; R33 AI138280 United States AI NIAID NIH HHS
المشرفين على المادة: 0 (Anti-Bacterial Agents)
0 (Antitubercular Agents)
0 (Bacterial Proteins)
0 (Diarylquinolines)
0 (Glyoxylates)
78846I289Y (bedaquiline)
JQ39C92HH6 (glyoxylic acid)
تواريخ الأحداث: Date Created: 20201201 Date Completed: 20201221 Latest Revision: 20210514
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC7705017
DOI: 10.1038/s41467-020-19959-4
PMID: 33257709
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-020-19959-4