Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish.

Pulmonary infections caused by are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of infection is the recent evidence of human-to-human transmission of the infection. is a naturally multidrug-resistant fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multidrug-resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic , BDQ was highly efficacious in a zebrafish model of infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from -induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. Mode-of-action studies revealed that BDQ triggered a rapid depletion of ATP in , consistent with the drug targeting the FF ATP synthase. Importantly, despite a failure to select for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in conferred high resistance, thus resolving the target of BDQ in Overall, this study indicates that BDQ is active against and and should be considered for clinical use against the difficult-to-manage pulmonary infections.