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Mol Microbiol. 2014 Feb;91(3):538-47. doi: 10.1111/mmi.12476. Epub 2014 Jan 9.

A silent mutation in mabA confers isoniazid resistance on Mycobacterium tuberculosis.

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Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655, Japan.


Drug resistance in Mycobacterium tuberculosis (Mtb) is caused by mutations in restricted regions of the genome. Mutations in katG, the promoter region of the mabA-inhA operon, and inhA are those most frequently responsible for isoniazid (INH) resistance. Several INH-resistant (INH(r) ) Mtb clinical isolates without mutations in these regions have been described, however, indicating that there are as yet undetermined mechanisms of INH resistance. We identified the mabA(g609a) silent mutation in a significant number of INH(r)  Mtb clinical isolates without known INH resistance mutations. A laboratory strain, H37Rv, constructed with mabA(g609a) , was resistant to INH. We show here that the mabA(g609a) mutation resulted in the upregulation of inhA, a gene encoding a target for INH, converting the region adjacent to the mutation into an alternative promoter for inhA. The mabA(g609a) silent mutation results in a novel mechanism of INH resistance, filling in a missing piece of INH resistance in Mtb.

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