Discovery of a Novel Mycobacterial F‐ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines
Adam Hotra, Priya Ragunathan, Pearly Shuyi Ng, Pattarakiat Seankongsuk, Amaravadhi Harikishore, Jickky Palmae Sarathy, Wuan Geok Saw, Umayal Lakshmanan, Patcharaporn Sae‐Lao, Nitin Pal Kalia, Joon Shin, Revathy Kalyanasundaram, Sivaraj Anbarasu, Krupakar Parthasarathy, Chaudhari Namrata Pradeep, Harshyaa Makhija, Peter Dröge, Anders Poulsen, Jocelyn Hui Ling Tan, Kévin Pethe, Thomas Dick, Roderick W. Bates, Gerhard Grüber
Abstract
-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.