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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963887/ https://www.ncbi.nlm.nih.gov/pubmed/31835707 http://dx.doi.org/10.3390/antibiotics8040261 |
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author | Sarathy, Jickky Palmae Gruber, Gerhard Dick, Thomas |
author_facet | Sarathy, Jickky Palmae Gruber, Gerhard Dick, Thomas |
author_sort | Sarathy, Jickky Palmae |
collection | PubMed |
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 α(3)β(3)-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 α(3)β(3)-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. |
format | Online Article Text |
id | pubmed-6963887 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69638872020-01-27 Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline Sarathy, Jickky Palmae Gruber, Gerhard Dick, Thomas Antibiotics (Basel) Review 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 α(3)β(3)-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 α(3)β(3)-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. MDPI 2019-12-11 /pmc/articles/PMC6963887/ /pubmed/31835707 http://dx.doi.org/10.3390/antibiotics8040261 Text en © 2019 by the authors. 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/). |
spellingShingle | Review Sarathy, Jickky Palmae Gruber, Gerhard Dick, Thomas Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline |
title | 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_short | 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 |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963887/ https://www.ncbi.nlm.nih.gov/pubmed/31835707 http://dx.doi.org/10.3390/antibiotics8040261 |
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