Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines
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 nov...
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Science::Biological sciences::Biochemistry ATP Synthesis Drug Discovery |
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Science::Biological sciences::Biochemistry ATP Synthesis Drug Discovery 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 Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines |
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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. |
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School of Biological Sciences 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 |
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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 |
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Hotra, Adam |
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Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines |
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Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines |
title_full |
Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines |
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Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines |
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Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines |
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discovery of a novel mycobacterial f-atp synthase inhibitor and its potency in combination with diarylquinolines |
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2021 |
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https://hdl.handle.net/10356/149233 |
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sg-ntu-dr.10356-1492332023-02-28T17:06:22Z Discovery of a novel mycobacterial F-ATP synthase inhibitor and its potency in combination with diarylquinolines 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 School of Biological Sciences School of Physical and Mathematical Sciences Lee Kong Chian School of Medicine (LKCMedicine) Interdisciplinary Graduate School (IGS) Nanyang Institute of Technology in Health and Medicine Science::Biological sciences::Biochemistry ATP Synthesis Drug Discovery 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. National Research Foundation (NRF) Accepted version This research was supported by the National ResearchFoundation (NRF) Singapore,NRF Competitive Research Programme (CRP), Grant Award Number NRF-CRP18-2017-01. A. Hotra is grateful to receive an IGS PremiumScholarship,Institute of Technology in Health and Medicineat NTU,and J. P. Sarathy received aPhD scholarship from theSchool of Medicine,NUS,Singapore.Wethank Dr. YongxinLi for the X-ray crystallographic structure determinations. 2021-05-25T00:35:45Z 2021-05-25T00:35:45Z 2020 Journal 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. https://dx.doi.org/10.1002/anie.202002546 1433-7851 0000-0002-8364-0147 0000-0002-2039-4890 0000-0002-2276-7953 0000-0001-6552-1534 0000-0003-4778-452X 0000-0003-1010-8771 0000-0003-1846-800X 0000-0001-5447-738X 0000-0002-8723-244X 0000-0003-0916-8873 0000-0002-9604-9452 0000-0002-8115-4970 0000-0002-5730-8319 https://hdl.handle.net/10356/149233 10.1002/anie.202002546 32337801 2-s2.0-85085610251 32 59 13295 13304 en NRF-CRP18-2017-01 Angewandte Chemie International edition 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. application/pdf |