Please use this identifier to cite or link to this item: https://doi.org/10.3390/antibiotics8040261
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dc.titleRe-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline
dc.contributor.authorSarathy, J.P.
dc.contributor.authorGruber, G.
dc.contributor.authorDick, T.
dc.date.accessioned2021-12-06T04:19:42Z
dc.date.available2021-12-06T04:19:42Z
dc.date.issued2019
dc.identifier.citationSarathy, J.P., Gruber, G., Dick, T. (2019). Re-understanding the mechanisms of action of the anti-mycobacterial drug bedaquiline. Antibiotics 8 (4) : 261. ScholarBank@NUS Repository. https://doi.org/10.3390/antibiotics8040261
dc.identifier.issn2079-6382
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/209508
dc.description.abstractBedaquiline (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 ?3?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 ?-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the ?3?3-headpiece. However, this mechanism is controversial as the drug’s binding affinity for the isolated ?-subunit protein is moderate and spontaneous resistance mutants in the ?-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 ?-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ’s anti-mycobacterial activity. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
dc.publisherMDPI AG
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceScopus OA2019
dc.subjectBedaquiline
dc.subjectC-subunit
dc.subjectDiarylquinoline
dc.subjectF-ATP synthase
dc.subjectTBAJ-876
dc.subjectTuberculosis
dc.subjectUncoupler
dc.subject?-subunit
dc.typeReview
dc.contributor.departmentDEPT OF MICROBIOLOGY & IMMUNOLOGY
dc.description.doi10.3390/antibiotics8040261
dc.description.sourcetitleAntibiotics
dc.description.volume8
dc.description.issue4
dc.description.page261
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