Affiliation:
1. Molecular Medicine Program The Hospital for Sick Children Toronto ON Canada
2. Department of Medical Biophysics The University of Toronto Toronto ON Canada
3. Institut für Pharmazie Martin‐Luther‐Universität Halle‐Wittenberg Halle, Saale Germany
4. Department of Biochemistry The University of Toronto Toronto ON Canada
Abstract
AbstractMycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug‐resistant tuberculosis but suffers from off‐target effects and is susceptible to resistance mutations. Consequently, both new and improved mycobacterial ATP synthase inhibitors are needed. We used electron cryomicroscopy and biochemical assays to study the interaction of Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ‐876 and the squaramide inhibitor SQ31f. The aryl groups of TBAJ‐876 improve binding compared with BDQ, while SQ31f, which blocks ATP synthesis ~10 times more potently than ATP hydrolysis, binds a previously unknown site in the enzyme's proton‐conducting channel. Remarkably, BDQ, TBAJ‐876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria.
Funder
Deutsche Forschungsgemeinschaft
Publisher
Springer Science and Business Media LLC
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience
Cited by
6 articles.
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