Rationale Documents

Bedaquiline (TMC207) is a diarylquinoline, a new class of anti-tuberculosis (TB) drugs, approved as an oral treatment as part of combination therapy for multidrug-resistant (MDR) TB. It has a novel mode of action (specific inhibition of mycobacterial adenosine triphosphate [ATP] synthase) which is an essential enzyme for M. tuberculosis. Bedaquiline has a long terminal half-life (5 months) and is highly protein bound (>99.9%). It has bactericidal effects for both replicating and non-replicating mycobacteria. The in vitro spectrum of bedaquiline is specific for mycobacteria and includes M. tuberculosis as well as other medically important species such as M. abscessus and the M. avium-intracellulare complex. High-level resistance mechanisms against bedaquiline described so far are due to specific mutations in the atpE gene coding for the ATP synthase target. Mechanisms described to mediate low level resistance are specific mutations in the Rv0678 gene, regulating the expression of the MmpS5-MmpL5 efflux pump and a cytoplasmic peptidase encoded by pepQ.