Discovery of a novel Mycobacterial F‐ATP synthase inhibitor and its potency in combination with diarylquinolines

The F 1 F O -ATP synthase is required for growth and viability of Mycobacterium tuberculosis . Bedaquiline validated this target clinically. We showed recently that a mycobacterium-specific loop of the enzyme's rotary gamma subunit plays a role in coupling of ATP synthesis within the enzyme complex. Here, we report the discovery of a novel antimycobacterial, termed GaMF1, targeting this gamma subunit loop. Biochemical and Nuclear Magnetic Resonance 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.