Multiplexed transcriptional repression identifies a network of bactericidal interactions between mycobacterial respiratory complexes.

remains a leading cause of infectious disease morbidity and mortality for which new drug combination therapies are needed. Combinations of respiratory inhibitors can have synergistic or synthetic lethal interactions with sterilizing activity, suggesting that regimens with multiple bioenergetic inhibitors could shorten treatment times. However, realizing this potential requires an understanding of which combinations of respiratory complexes, when inhibited, have the strongest consequences on bacterial growth and viability.

Transcriptional Inhibition of the FF-Type ATP Synthase Has Bactericidal Consequences on the Viability of Mycobacteria.

Bedaquiline, an inhibitor of the mycobacterial ATP synthase, has revolutionized the treatment of infection. Although a potent inhibitor, it is characterized by poorly understood delayed time-dependent bactericidal activity. Here, we demonstrate that in contrast to bedaquiline, the transcriptional inhibition of the ATP synthase in and has rapid bactericidal activity.