Komm, O. D.; Tyagi, S.; Garcia, A.; Almeida, D. V.; Chang, Y. S.; Li, S.-Y.; Castillo, J. R.; Converse, P. J.; Black, T.; Fotouhi, N.; Nuermberger, E. L.

The clinical efficacy of combination drug regimens containing the first generation diarylquinoline (DARQ) bedaquiline in the treatment of multidrug-resistant tuberculosis has validated ATP synthesis as a vulnerable pathway in Mycobacterium tuberculosis. New DARQs in clinical development may be even more effective than bedaquiline, including against emerging bedaquiline-resistant strains. Telacebec (T) is a novel cytochrome bc1:aa3 oxidase inhibitor that also inhibits ATP synthesis. Based on its demonstrated efficacy as a monotherapy in mice and in a phase 2a clinical trial, we used an established BALB/c mouse model of tuberculosis (TB) to test the contribution of T to novel combination therapies against two strains of M. tuberculosis (H37Rv and HN878) in an effort to find more effective regimens. Overall, T was more effective in regimens against the HN878 strain than against the H37Rv strain, a finding that supports the greater vulnerability of the former strain to T and to genetic depletion of QcrB. Against both strains, combinations of a DARQ, clofazimine (CFZ), and T were highly bactericidal. However, only against HN878 did T contribute synergistically, whereas an antagonistic effect was observed against H37Rv. These results demonstrate the therapeutic potential of T and highlight how differences in the susceptibility of M. tuberculosis strains could lead to different conclusions about a drug\'s potential contribution to novel drug regimens.