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

Pulmonary infections caused byMycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern ofM. abscessus infection is the recent evidence of human-to-human transmission of the infection.M. abscessus 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 againstM. abscessus 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 bacteriostaticin vitro , BDQ was highly efficacious in a zebrafish model ofM. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae fromM. abscessus -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 inM. abscessus in vitro , consistent with the drug targeting the Fo F1 ATP synthase. Importantly, despite a failure to selectin vitro for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions inatpE conferred high resistance, thus resolving the target of BDQ inM. abscessus . Overall, this study indicates that BDQ is active againstM. abscessus in vitro andin vivo and should be considered for clinical use against the difficult-to-manageM. abscessus pulmonary infections.