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

Abstract

Pulmonary infections caused by <i>Mycobacterium abscessus</i> are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of <i>M. abscessus</i> infection is the recent evidence of human-to-human transmission of the infection. <i>M. abscessus</i> 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 <i>M. abscessus</i> 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 <i>in vitro</i>, BDQ was highly efficacious in a zebrafish model of <i>M. abscessus</i> infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from <i>M. abscessus</i>-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 <i>M. abscessus</i><i>in vitro</i>, consistent with the drug targeting the F_oF₁ ATP synthase. Importantly, despite a failure to select <i>in vitro</i> for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in <i>atpE</i> conferred high resistance, thus resolving the target of BDQ in <i>M. abscessus</i> Overall, this study indicates that BDQ is active against <i>M. abscessus</i><i>in vitro</i> and <i>in vivo</i> and should be considered for clinical use against the difficult-to-manage <i>M. abscessus</i> pulmonary infections.