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

Abstract

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.

In Vitro Susceptibility Testing of Bedaquiline against Mycobacterium abscessus Complex

“…massiliense, and from 0.031 to 0.125 g/ml for M. abscessus subsp. bolletii (24). MIC 50 values were 0.06 g/ml for M. abscessus subsp.…”

“…A later small study performed outside the United States (and not using the current CLSI antimicrobial susceptibility testing [AST] guidelines), showed bedaquiline MICs of 0.062 and 0.25 g/ml for two reference strains of M. abscessus (11). The same investigators also studied other RGM species (1 to The 2017 study by Dupont et al used a zebrafish preclinical mode to show that bedaquiline caused a rapid depletion of ATP in isolates of M. abscessus-infected zebrafish (24). This action was consistent with the drug targeting the F o F 1 ATP synthase.…”

“…Amino acid substitutions led to high resistance in bedaquiline. The authors speculated this was due to the structured interference of the mutations with the binding of bedaquiline (24).…”

Moxifloxacin efficacy againstMycobacterium abscessus in vivousing zebrafish model

“…Although positive impact on inhibiting CFU was observed, there was no significant result even. Although the CFU was recommended for ZF model [19,24], in our study it is useless for assessing drug activity in vivo using ZF model. Experimental method may need to be improved.…”

“…Further more, the present study reports the usefulness of ZF as a preclinical model to evaluate in real time the efficacy of MFX and AZM against M. abscessus infection. Since ZF have been successfully used in the past to test the efficacy of three clinically relevant drugs, clarithromycin, imipenem and bedaquiline [19,24,25], future studies should address the in vivo efficacies of other drugs using the zebrafish model of M. abscessus infection.…”