Bedaquiline (Sirturo) is approved for MDR-TB and XDR-TB. Its novel mechanism of action, distinct from all existing anti-TB drugs, is:
- A Inhibition of mycobacterial DNA gyrase (different subunit than fluoroquinolones target)
- B Inhibition of mycolic acid synthesis at the same target as isoniazid (InhA), but active against InhA-mutant INH-resistant strains
- C Blockade of the MmpL3 trehalose monomycolate transporter, preventing mycolate export to the mycobacterial outer membrane
- D Specific inhibition of mycobacterial ATP synthase (subunit c of the F1F0-ATPase), depleting ATP and disrupting proton motive force in both replicating and dormant bacilli ✓
Explanation
Bedaquiline is a diarylquinoline that specifically targets the subunit c of mycobacterial ATP synthase (F0 proton channel). By blocking proton transport through F0, it prevents ATP synthesis, starving Mycobacterium tuberculosis of energy. Critically, it is active against both metabolically active (replicating) and dormant (non-replicating persister) bacilli, addressing one of the main reasons for prolonged TB treatment. MmpL3 is the target of SQ109; DNA gyrase is targeted by fluoroquinolones; InhA is targeted by isoniazid. Bedaquiline is used in all-oral regimens for MDR-TB per 2022 WHO guidelines.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.