School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Republic of Singapore.
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore.
Angew Chem Int Ed Engl. 2020 Aug 3;59(32):13295-13304. doi: 10.1002/anie.202002546. Epub 2020 May 26.
The F F -ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.
F F -ATP 合酶是结核分枝杆菌生长和存活所必需的，也是经过验证的临床靶点。该酶的旋转γ亚基的一个分枝杆菌特异性环在酶复合物内的 ATP 合成偶联中发挥作用。我们报告了一种新型抗分枝杆菌化合物 GaMF1 的发现，该化合物靶向该γ亚基环。生化和 NMR 研究表明，GaMF1 通过与环结合来抑制 ATP 合酶的活性。GaMF1 具有杀菌作用，对耐多药和贝达喹啉的菌株均有效。该支架上的化学研究揭示了动态结构活性关系，并提供了具有纳摩尔效力的类似物。将 GaMF1 与贝达喹啉或新型二芳基喹啉类似物联合使用可在人胚胎干细胞报告检测中增强活性而不诱导遗传毒性或表型变化。这些结果表明，GaMF1 为发现新型抗结核 F-ATP 合酶抑制剂提供了有吸引力的先导化合物。
