A potent phenylalkylamine disrupts membrane bioenergetics and augments anti-mycobactericidal properties of bedaquiline. Phua et al

Combination therapies are widely employed for the treatment of mycobacterial infections due to their clinical efficacy and ability to impede resistance. Structure-activity relationship studies conducted on the phenylalkylamine scaffold of verapamil (VP) yielded an analog with greater growth inhibitory activity than VP against Mtb and M. bovis BCG by 20- to 30-fold, and Mab abscessus by 60-fold. The analog synergized with the F1Fo-ATP synthase inhibitor bedaquiline (BDQ) in checkerboard assays and augmented the bactericidal properties of BDQ by a remarkable 104-fold reduction in colony formation units (CFUs) of M. bovis BCG and Mab abscessus. Using live cell bioorthogonal imaging techniques, in vitro biochemical and genetic assays, the bactericidal activity of the analog is attributed to the perturbation of membrane bioenergetics and disruption of mycobacterial respiration. Overall, its promising activity profile, mode of action and synergistic interaction with BDQ support further exploration of the phenylalkylamine scaffold as a valuable source of potential leads for antimycobacterial drug discovery.