Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline

Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme’s c-ring to block its rotation, thus inhibiting ATP synthesis in the en...

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Main Authors: Sarathy, Jickky Palmae, Gruber, Gerhard, Dick, Thomas
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2020
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Online Access:https://hdl.handle.net/10356/138546
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spelling sg-ntu-dr.10356-1385462023-02-28T16:57:47Z Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline Sarathy, Jickky Palmae Gruber, Gerhard Dick, Thomas School of Biological Sciences Science::Biological sciences::Biochemistry Science::Biological sciences::Molecular biology Tuberculosis Bedaquiline Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme’s c-ring to block its rotation, thus inhibiting ATP synthesis in the enzyme’s catalytic α3β3-headpiece. An indirect mechanism involves BDQ uncoupling electron transport in the electron transport chain from ATP synthesis at the F-ATP synthase. In a recently uncovered second direct mechanism, BDQ binds to the enzyme’s ε-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the α3β3-headpiece. However, this mechanism is controversial as the drug’s binding affinity for the isolated ε-subunit protein is moderate and spontaneous resistance mutants in the ε-subunit cannot be isolated. Recently, the new, structurally distinct BDQ analogue TBAJ-876 was utilized as a chemical probe to revisit BDQ’s mechanisms of action. In this review, we first summarize discoveries on BDQ’s mechanisms of action and then describe the new insights derived from the studies of TBAJ-876. The TBAJ-876 investigations confirm the c-ring as a target, while also supporting a functional role for targeting the ε-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ’s anti-mycobacterial activity. NRF (Natl Research Foundation, S’pore) Published version 2020-05-08T01:41:15Z 2020-05-08T01:41:15Z 2019 Journal Article Sarathy, J. P., Gruber, G., & Dick, T. (2019). Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline. Antibiotics, 8(4), 261-. doi:10.3390/antibiotics8040261 2079-6382 https://hdl.handle.net/10356/138546 10.3390/antibiotics8040261 31835707 2-s2.0-85077045802 4 8 en Antibiotics © 2019 The Author(s). Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences::Biochemistry
Science::Biological sciences::Molecular biology
Tuberculosis
Bedaquiline
spellingShingle Science::Biological sciences::Biochemistry
Science::Biological sciences::Molecular biology
Tuberculosis
Bedaquiline
Sarathy, Jickky Palmae
Gruber, Gerhard
Dick, Thomas
Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
description Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme’s c-ring to block its rotation, thus inhibiting ATP synthesis in the enzyme’s catalytic α3β3-headpiece. An indirect mechanism involves BDQ uncoupling electron transport in the electron transport chain from ATP synthesis at the F-ATP synthase. In a recently uncovered second direct mechanism, BDQ binds to the enzyme’s ε-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the α3β3-headpiece. However, this mechanism is controversial as the drug’s binding affinity for the isolated ε-subunit protein is moderate and spontaneous resistance mutants in the ε-subunit cannot be isolated. Recently, the new, structurally distinct BDQ analogue TBAJ-876 was utilized as a chemical probe to revisit BDQ’s mechanisms of action. In this review, we first summarize discoveries on BDQ’s mechanisms of action and then describe the new insights derived from the studies of TBAJ-876. The TBAJ-876 investigations confirm the c-ring as a target, while also supporting a functional role for targeting the ε-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ’s anti-mycobacterial activity.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Sarathy, Jickky Palmae
Gruber, Gerhard
Dick, Thomas
format Article
author Sarathy, Jickky Palmae
Gruber, Gerhard
Dick, Thomas
author_sort Sarathy, Jickky Palmae
title Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
title_short Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
title_full Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
title_fullStr Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
title_full_unstemmed Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
title_sort re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
publishDate 2020
url https://hdl.handle.net/10356/138546
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