Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis
| Autor: | Adrie J. C. Steyn, Joel N. Glasgow, Dirk A. Lamprecht, Simon Rousseau, Khushboo Borah, John H. Adamson, Rukaya Asmal, Dany J. V. Beste, James C. Sacchettini, Bei Shi Lee, Inna Krieger, Kevin Pethe, Jared S. Mackenzie |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Science Citric Acid Cycle Antitubercular Agents General Physics and Astronomy Oxidative phosphorylation Article Oxidative Phosphorylation General Biochemistry Genetics and Molecular Biology Carbon Cycle Mycobacterium tuberculosis 03 medical and health sciences Substrate-level phosphorylation chemistry.chemical_compound 0302 clinical medicine Bacterial Proteins Antibiotics Tuberculosis Glycolysis Diarylquinolines Cellular microbiology Multidisciplinary biology Chemistry Glyoxylates General Chemistry Metabolism biology.organism_classification Anti-Bacterial Agents Cell biology Citric acid cycle 030104 developmental biology Gluconeogenesis Bedaquiline Energy Metabolism 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-19959-4 |
| Popis: | 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 13C 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. Bedaquiline (BDQ) is a known tuberculosis treatment, but the precise mechanism of cell death is unclear. Here, the authors explore the metabolic profiles of M. tuberculosis upon BDQ treatment and find reliance on glycolysis and synergistic cell death when oxidative phosphorylation is also targeted. |
| Databáze: | OpenAIRE |
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