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Open AccessReview

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

1
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
2
School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
3
Center for Drug Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
4
Department of Medical Sciences, Hackensack Meridian School of Medicine at Seton Hall University, Nutley, NJ 07110, USA
5
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
*
Author to whom correspondence should be addressed.
Antibiotics 2019, 8(4), 261; https://doi.org/10.3390/antibiotics8040261
Received: 16 November 2019 / Accepted: 7 December 2019 / Published: 11 December 2019
(This article belongs to the Special Issue Antibiotics against Tuberculosis)
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. View Full-Text
Keywords: tuberculosis; Bedaquiline; diarylquinoline; TBAJ-876; F-ATP synthase; c-subunit; ε-subunit; uncoupler tuberculosis; Bedaquiline; diarylquinoline; TBAJ-876; F-ATP synthase; c-subunit; ε-subunit; uncoupler
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MDPI and ACS Style

Sarathy, J.P.; Gruber, G.; Dick, T. Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline. Antibiotics 2019, 8, 261. https://doi.org/10.3390/antibiotics8040261

AMA Style

Sarathy JP, Gruber G, Dick T. Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline. Antibiotics. 2019; 8(4):261. https://doi.org/10.3390/antibiotics8040261

Chicago/Turabian Style

Sarathy, Jickky P.; Gruber, Gerhard; Dick, Thomas. 2019. "Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline" Antibiotics 8, no. 4: 261. https://doi.org/10.3390/antibiotics8040261

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