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.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) [1,2], is the leading infectious disease killer worldwide and a major global health concern [1,3]
ATP synthesis, the process targeted by BDQ, occurs through a complex metabolic pathway known as oxidative phosphorylation
The pumping of protons generates a transmembrane pH gradient and contributes to the membrane potential, both of which are components of the proton motive force [38]. This force drives the rotation of the F-ATP synthase c-ring, which drives ATP synthesis at the enzyme’s α3 β3 catalytic headpiece via the enzyme’s central stalk subunits γ and ε [38,39,40,41]
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) [1,2], is the leading infectious disease killer worldwide and a major global health concern [1,3]. Concentration (MIC) of 0.002–0.013 μg/mL [10,11]) This potent activity holds true in vivo where. BDQ displays bactericidal activity against non-replicating Mtb at therapeutically attainable concentrations [14,15]. New BDQ-containing drug regimens are currently being explored in Phase III clinical trials, such as the STREAM and SimpliciTB trials [20]. One such trial, the Nix-TB trial, resulted in the recent US FDA approval of the Antibiotics. BDQ-pretomanid-linezolid six months, all-oral regimen for the treatment of drug-resistant TB [21,22].
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