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

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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 ( IF 2.5 ) Pub Date : 2023-11-20 , DOI: 10.1016/j.bbrc.2023.149249
Alexander Krah ₁ , Priya Ragunathan ₂ , Peter J Bond ₃ , Gerhard Grüber ₄

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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 F₁F_O-ATP synthase. Molecular dynamics simulations and binding free energy calculations highlight the differences in drug-binding of the M. abscessus and M. smegmatis F_O-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.

中文翻译：

脓肿分枝杆菌 F-ATP 合酶亚基 ac 界面的变异改变了抗结核药物贝达喹啉的结合和效力

抗结核治疗药物贝达喹啉 (BDQ) 用于对抗脓肿分枝杆菌。在脓肿分枝杆菌中，BDQ 仅具有抑菌作用，并且与结核分枝杆菌或耻垢分枝杆菌相比效力较低。在这里，我们证明了它对脓肿分枝杆菌内翻囊泡（包括 F ₁ F _O -ATP 合酶）的 ATP 合成抑制作用降低。分子动力学模拟和结合自由能计算突出了脓肿分枝杆菌和耻垢分枝杆菌F _O结构域在滞后位点的药物结合差异，药物在该位点发挥其机械作用，抑制 ATP 合成。这些数据为改进抗脓肿分枝杆菌BDQ类似物铺平了道路。

更新日期：2023-11-24

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