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Title: Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
Authors: Sarathy, Jickky Palmae
Gruber, Gerhard
Dick, Thomas
Keywords: Science::Biological sciences::Biochemistry
Science::Biological sciences::Molecular biology
Issue Date: 2019
Source: 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
Journal: Antibiotics
Abstract: 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.
ISSN: 2079-6382
DOI: 10.3390/antibiotics8040261
Rights: © 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 (
Fulltext Permission: open
Fulltext Availability: With Fulltext
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