Mycobacterium abscessus WhiB7 regulates a species -specific repertoire of genes to confer extreme antibiotic resistance [PublishAheadOfPrint]

Mycobacterium abscessus causes acute and chronic broncho-pulmonary infection in patients with chronic lung damage, of which cystic fibrosis (CF) patients are particularly vulnerable. The major threat posed by this organism is its high intrinsic antibiotic resistance. A typical treatment regimen involves a 6-12 month long combination therapy of clarithromycin and amikacin, with cure rates below 50% and multiple side effects, especially due to amikacin. In the present work we show that M. abscessus whiB7, a homologue of M. tuberculosis and M. smegmatis whiB7 with previously demonstrated effects on intrinsic antibiotic resistance, is strongly induced when exposed to clinically relevant antibiotics that target the ribosome - erythromycin, clarithromycin, amikacin, tetracycline and spectinomycin. Deletion of M. abscessus whiB7 results in sensitivity to all of the above antibiotics. Further, we have defined and compared the whiB7 regulon of M. abscessus with the closely related (non-tuberculous mycobacterium) NTM, M. smegmatis to demonstrate the induction of species-specific repertoire of genes. Further we show that one such gene, eis2, is specifically induced in M. abscessus by whiB7, and contributes to its higher levels of intrinsic amikacin resistance. This species-specific pattern of gene induction could account for the differences in drug susceptibilities to other antibiotics and between different mycobacterial species.

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