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. 2020 Aug 3;59(32):13295-13304.
doi: 10.1002/anie.202002546. Epub 2020 May 26.

Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines

Adam Hotra  1   2   3 , Priya Ragunathan  2 , Pearly Shuyi Ng  4 , Pattarakiat Seankongsuk  1 , Amaravadhi Harikishore  1   2 , Jickky Palmae Sarathy  5 , Wuan-Geok Saw  2 , Umayal Lakshmanan  4 , Patcharaporn Sae-Lao  1 , Nitin Pal Kalia  6 , Joon Shin  2 , Revathy Kalyanasundaram  7 , Sivaraj Anbarasu  7 , Krupakar Parthasarathy  7 , Chaudhari Namrata Pradeep  2 , Harshyaa Makhija  2 , Peter Dröge  2 , Anders Poulsen  4 , Jocelyn Hui Ling Tan  4 , Kevin Pethe  2   6 , Thomas Dick  5   8 , Roderick W Bates  1 , Gerhard Grüber  2
Affiliations

Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines

Adam Hotra et al. Angew Chem Int Ed Engl. .

Abstract

The F1 FO -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.

Keywords: ATP synthesis; F-ATP synthase; drug discovery; inhibitors; tuberculosis.

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References

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