Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis

Jared S. Mackenzie, Dirk A. Lamprecht, Rukaya Asmal, John H. Adamson, Khushboo Borah, Dany J. V. Beste, Bei Shi Lee, Kevin Pethe, Simon Rousseau, Inna Krieger, James C. Sacchettini, Joel N. Glasgow and Adrie J. C. Steyn ()
Additional contact information
Jared S. Mackenzie: Africa Health Research Institute
Dirk A. Lamprecht: Janssen Pharmaceutica, Global Public Health
Rukaya Asmal: Africa Health Research Institute
John H. Adamson: Africa Health Research Institute
Khushboo Borah: Faculty of Health and Medical Sciences, University of Surrey
Dany J. V. Beste: Faculty of Health and Medical Sciences, University of Surrey
Bei Shi Lee: Nanyang Technological University
Kevin Pethe: Nanyang Technological University
Simon Rousseau: Texas A&M University, Department of Biochemistry and Biophysics
Inna Krieger: Texas A&M University, Department of Biochemistry and Biophysics
James C. Sacchettini: Texas A&M University, Department of Biochemistry and Biophysics
Joel N. Glasgow: University of Alabama at Birmingham
Adrie J. C. Steyn: Africa Health Research Institute

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19959-4

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