Bedaquiline is a novel anti-TB drug used for MDR-TB and XDR-TB. It has a unique mechanism unlike any existing anti-TB agent. What is this mechanism?

• A Bedaquiline inhibits decaprenylphosphoryl-D-arabinose (DPA) synthase, blocking arabinogalactan synthesis in the mycobacterial cell wall
• B Bedaquiline inhibits InhA (enoyl-ACP reductase), blocking mycolic acid synthesis like isoniazid but through a different binding site
• C Bedaquiline specifically inhibits the mycobacterial ATP synthase (subunit c of the F0 component), preventing ATP synthesis and collapsing the proton gradient essential for mycobacterial energy metabolism ✓
• D Bedaquiline inhibits GyrB subunit of DNA gyrase with 1000-fold selectivity for mycobacterial over human topoisomerase II

Explanation

Bedaquiline (diarylquinoline) has an entirely novel mechanism: it selectively inhibits the mycobacterium-specific ATP synthase, specifically by binding to the oligomeric c-ring (Fo subunit) of mycobacterial F1Fo ATP synthase. This prevents proton translocation through the Fo channel, collapsing the proton motive force and ATP synthesis. M. tuberculosis relies heavily on oxidative phosphorylation for ATP synthesis (it cannot efficiently use glycolysis), making ATP synthase inhibition highly lethal. Bedaquiline has long tissue half-life (5+ months due to CYP3A4 hepatic metabolism and lipid partitioning) and is active against both replicating and non-replicating persisters. It is used in WHO-recommended MDR-TB regimen BPaL (bedaquiline + pretomanid + linezolid). Major concern: QT prolongation via hERG channel block and drug-drug interaction with other QT-prolonging agents.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.