Variations of the Mycobacterium abscessus F-ATP synthase subunit a-c interface alter binding and potency of the anti-TB drug bedaquiline

Variations of the Mycobacterium abscessus F-ATP synthase subunit a-c interface alter binding and potency of the anti-TB drug bedaquiline

Biochemical and Biophysical Research Communications

10.1016/j.bbrc.2023.149249

http://dx.doi.org/10.1016/j.bbrc.2023.149249

Alexander Krah, Priya Ragunathan, Peter J. Bond, Gerhard Gruber

20 November 2023

Krah, A., Ragunathan, P., Bond, P. J., Grüber, G. (2024). Variations of the Mycobacterium abscessus F-ATP synthase subunit a-c interface alter binding and potency of the anti-TB drug bedaquiline. Biochemical and Biophysical Research Communications, 690, 149249. https://doi.org/10.1016/j.bbrc.2023.149249

The anti-tuberculosis therapeutic bedaquiline (BDQ) is used against Mycobacterium abscessus. In M. abscessus BDQ is only bacteriostatic and less potent compared to M. tuberculosis or M. smegmatis. Here we demonstrate its reduced ATP synthesis inhibition against M. abscessus inside-out vesicles, including the F1FO-ATP synthase. Molecular dynamics simulations and binding free energy calculations highlight the differences in drug-binding of the M. abscessus and M. smegmatis FO-domain at the lagging site, where the drug deploys its mechanistic action, inhibiting ATP synthesis. These data pave the way for improved anti-M. abscessus BDQ analogs.

Publisher Copyright

This research / project is supported by the National Research Foundation (NRF) Singapore, /NRF Competitive Research Programme (CRP)

This research is supported by core funding from: A*STAR - Bioinformatics Institute
Grant Reference no. : NA

https://oar.a-star.edu.sg/communities-collections/articles/20709

0006-291X

Bioinformatics Institute

https://www.sciencedirect.com/science/article/pii/S0006291X23013438?via%3Dihub