Identification of novel mutations associated with bedaquiline resistance in Mycobacterium marinum

Due to the rapid increase in non-tuberculous mycobacterial (NTM) infections worldwide, there is a need to develop new antibiotics and discover mechanisms of resistance.A new study reported in zoonotic disease It aims to understand the mechanisms of bedaquiline resistance in the model NTM species Mycobacterium marinum (M. marinum).

Mycobacterium marinum strains were subjected to mutant selection with varying concentrations of BDQ. After three rounds of evolution, 58 BDQ-resistant mutants were isolated and subjected to WGS. Results were confirmed by PCR and Sanger sequencing.

Seven Genetic mutation identified among these mutants. The highest drug resistance (6- to 10-fold MIC) was associated with mutations in AtpB, the major biochemical target of BDQ in Mtb. Numerous mutations and insertions mapped to the gene MMAR_1007(46/58) encoding the homologue of Rv0678 (MmpR) in Mtb. Over 93% of the mutants (54/58) contained a single mutation (G563A) in MMAR_4049 encoding the integral membrane protein YrbE3A-1.

Both target- and efflux-based actions contribute to BDQ resistance in M. marinum. These findings may aid in the development of new potent anti-NTM (BDQ-based) drug regimens and diagnostic assays to detect BDQ-resistant M. marinum.