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Identification of novel mutations associated with clofazimine resistance in Mycobacterium abscessus

By Yuanyuan Chen, Jiazhen Chen, Shuo Zhang, Wanliang Shi, Wenhong Zhang, Min Zhu, Ying Zhang

Posted 04 Mar 2018
bioRxiv DOI: 10.1101/276022

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 and shows synergistic activity when given with amikacin, but the mechanism of resistance to clofazimine in Mab is unknown. To investigate the molecular basis of clofazimine resistance in Mab, e isolated 29 Mab mutants resistant to clofazimine, and subjected them to whole genome sequencing to identify possible mutations associated with clofazimine resistance. Mutations in MAB_2299c gene which encodes possible transcriptional regulatory protein were identified in 23 of the 29 clofazimine-resistant mutants. In addition, 6 mutations in MAB_1483 were found in 21 of the 29 mutants, and one mutation in MAB_0540 was found in 16 of the 29 mutants. Mutations in MAB_0416c, MAB_4099c, MAB_2613, MAB_0409, MAB_1426 were also associated with clofazimine resistance 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. Future studies are needed to address the role of the identified mutations in clofazimine resistance in Mab. Our findings have implications for developing a rapid molecular test for detecting clofazimine resistance in this organism.

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