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Discovery of a Novel Mycobacterial F‐ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines
Author(s) -
Hotra Adam,
Ragunathan Priya,
Ng Pearly Shuyi,
Seankongsuk Pattarakiat,
Harikishore Amaravadhi,
Sarathy Jickky Palmae,
Saw WuanGeok,
Lakshmanan Umayal,
SaeLao Patcharaporn,
Kalia Nitin Pal,
Shin Joon,
Kalyanasundaram Revathy,
Anbarasu Sivaraj,
Parthasarathy Krupakar,
Pradeep Chaudhari Namrata,
Makhija Harshyaa,
Dröge Peter,
Poulsen Anders,
Tan Jocelyn Hui Ling,
Pethe Kevin,
Dick Thomas,
Bates Roderick W.,
Grüber Gerhard
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202002546
Subject(s) - bedaquiline , atp synthase , antimycobacterial , mycobacterium tuberculosis , biochemistry , protein subunit , enzyme , drug discovery , glutamine amidotransferase , chemistry , biology , tuberculosis , gene , amino acid , pathology , glutamine , medicine
Abstract The F 1 F O ‐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.