Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines
Mycobacteria, 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‐t...
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Veröffentlicht in: | The EMBO journal 2023-08, Vol.42 (15), p.e113687-n/a |
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Zusammenfassung: | Mycobacteria, 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.
Synopsis
The diarylquinoline bedaquiline is a mycobacterial ATP synthase inhibitor used to treat tuberculosis. Here, high‐resolution electron cryomicroscopy reveals how the second generation diarylquinoline TBAJ‐876 and the squaramide SQ31f inhibit ATP synthase.
High‐resolution cryoEM structure shows the role of TBAJ‐876's aryl groups in improving its binding to ATP synthase compared with bedaquiline.
SQ31f binds a previously unknown pocket in the ATP synthase proton‐conducting channel.
Bedaquiline, TBAJ‐876, and SQ31f induce similar conformational changes in ATP synthase.
Bedaquiline, TBAJ‐876, and TBAJ‐587, but not the squaramide SQ31f, uncouple a transmembrane electrochemical proton gradient in mycobacterial inverted membrane vesicles.
Graphical Abstract
High‐resolution electron cryomicroscopy reveals that binding of a candidate tuberculosis drug and a different class of inhibitor to
M. smegmatis
ATP synthase induces similar conformational changes. |
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ISSN: | 0261-4189 1460-2075 1460-2075 |
DOI: | 10.15252/embj.2023113687 |