TY - JOUR
T1 - Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines
AU - Hotra, Adam
AU - Ragunathan, Priya
AU - Ng, Pearly Shuyi
AU - Seankongsuk, Pattarakiat
AU - Harikishore, Amaravadhi
AU - Sarathy, Jickky Palmae
AU - Saw, Wuan Geok
AU - Lakshmanan, Umayal
AU - Sae-Lao, Patcharaporn
AU - Kalia, Nitin Pal
AU - Shin, Joon
AU - Kalyanasundaram, Revathy
AU - Anbarasu, Sivaraj
AU - Parthasarathy, Krupakar
AU - Pradeep, Chaudhari Namrata
AU - Makhija, Harshyaa
AU - Dröge, Peter
AU - Poulsen, Anders
AU - Tan, Jocelyn Hui Ling
AU - Pethe, Kevin
AU - Dick, Thomas
AU - Bates, Roderick W.
AU - Grüber, Gerhard
N1 - Publisher Copyright:
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2020/8/3
Y1 - 2020/8/3
N2 - The F1FO-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.
AB - The F1FO-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.
KW - ATP synthesis
KW - drug discovery
KW - F-ATP synthase
KW - inhibitors
KW - tuberculosis
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U2 - 10.1002/anie.202002546
DO - 10.1002/anie.202002546
M3 - Article
C2 - 32337801
AN - SCOPUS:85085610251
SN - 1433-7851
VL - 59
SP - 13295
EP - 13304
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 32
ER -
