Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacteria that is quickly emerging as a global health concern. M. abscessus pulmonary infections are frequently intractable due to the high intrinsic resistance to most antibiotics. Therefore, there is an urgent need to discover effective pharmacological options for M. abscessus infections. In this study, the potency of the anti-tuberculosis drug Telacebec (Q203) was evaluated against M. abscessus. Q203 is a clinical-stage drug candidate targeting the sub-unit QcrB of the cytochrome bc1:aa3 terminal oxidase. We demonstrated that the presence of four naturally-occurring polymorphisms in the M. abscessus QcrB are responsible for the high resistance of the bacterium to Q203. Genetics reversion of the four polymorphism sensitized M. abscessus to Q203. While this study highlights the limitation of a direct drug repurposing approach of Q203 and related drugs for M. abscessus infections, it reveals that the M. abscessus cytochrome bc1:aa3 respiratory branch is sensitive to chemical inhibition.

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The anti-tuberculosis drug telacebec is ineffective against Mycobacterium abscessus . A recent study suggested that TB47, a telacebec analogue, potentiated the efficacy of clofazimine against M. abscessus . Here, we report that TB47 is not only ineffective against M. abscessus in vitro , it also does not potentiate the activity of clofazimine.