Novel Mutations Associated with Clofazimine Resistance in Mycobacterium abscessus [PublishAheadOfPrint]

Mycobacterium abscessus (Mab) is a major non-tuberculous mycobacterial (NTM) pathogen responsible for about 80% of all pulmonary infections caused by rapidly growing mycobacteria. Clofazimine is an effective drug active against Mab, but the mechanism of resistance to clofazimine in Mab is unknown. To investigate the molecular basis of clofazimine resistance in Mab. We isolated 29 Mab mutants resistant to clofazimine, and subjected them to whole genome sequencing to identify possible mutations associated with clofazimine resistance. We found that mutations in MAB_2299c gene which encodes possible transcriptional regulatory protein, MAB_1483 and MAB_0540 are most commonly associated with clofazimine resistance. In addition, mutations in MAB_0416c, MAB_4099c, MAB_2613, MAB_0409, and MAB_1426 were also associated with clofazimine resistance but in less frequency. Two identical mutations which are likely to be polymorphisms unrelated to clofazimine resistance were found in MAB_4605c and MAB_4323 in 13 mutants. We conclude that mutations in MAB_2299c, MAB_1483, and MAB_0540 are the major mechanisms of clofazimine resistance in Mab. Future studies are needed to address the role of the identified mutations in clofazimine resistance in Mab. Our findings have implications for understanding mechanisms of resistance of clofazimine and for rapid detection of clofazimine resistance in this organism.

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