Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/149233
Title: Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines
Authors: Hotra, Adam
Ragunathan, Priya
Ng, Pearly Shuyi
Seankongsuk, Pattarakiat
Harikishore, Amaravadhi
Sarathy, Jickky Palmae
Saw, Wuan-Geok
Lakshmanan, Umayal
Sae-Lao, 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 Wayland
Grüber, Gerhard
Keywords: Science::Biological sciences::Biochemistry
Issue Date: 2020
Source: Hotra, A., Ragunathan, P., Ng, P. S., Seankongsuk, P., Harikishore, A., Sarathy, J. P., Saw, W., Lakshmanan, U., Sae-Lao, P., Kalia, N. P., Shin, J., Kalyanasundaram, R., Anbarasu, S., Parthasarathy, K., Pradeep, C. N., Makhija, H., Dröge, P., Poulsen, A., Tan, J. H. L., ...Grüber, G. (2020). Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines. Angewandte Chemie International Edition, 59(32), 13295-13304. https://dx.doi.org/10.1002/anie.202002546
Project: NRF-CRP18-2017-01
Journal: Angewandte Chemie International edition
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.
URI: https://hdl.handle.net/10356/149233
ISSN: 1433-7851
DOI: 10.1002/anie.202002546
Rights: This is the peer reviewed version of the following article: Hotra, A., Ragunathan, P., Ng, P. S., Seankongsuk, P., Harikishore, A., Sarathy, J. P., Saw, W., Lakshmanan, U., Sae-Lao, P., Kalia, N. P., Shin, J., Kalyanasundaram, R., Anbarasu, S., Parthasarathy, K., Pradeep, C. N., Makhija, H., Dröge, P., Poulsen, A., Tan, J. H. L., ...Grüber, G. (2020). Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines. Angewandte Chemie International Edition, 59(32), 13295-13304, which has been published in final form at https://dx.doi.org/10.1002/anie.202002546. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Fulltext Permission: embargo_20210810
Fulltext Availability: With Fulltext
Appears in Collections:IGS Journal Articles
LKCMedicine Journal Articles
SBS Journal Articles
SPMS Journal Articles

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