A silent mutation in mabA confers isoniazid resistance on Mycobacterium tuberculosis

作者：Ando Hiroki; Miyoshi Akiyama Tohru; Watanabe Shinya; Kirikae Teruo

来源：Molecular Microbiology, 2014, 91(3): 538-547.

DOI：10.1111/mmi.12476

<jats:title>Summary</jats:title><jats:p>Drug resistance in <jats:italic><jats:styled-content style="fixed-case">M</jats:styled-content>ycobacterium tuberculosis</jats:italic> (<jats:italic><jats:styled-content style="fixed-case">Mtb</jats:styled-content></jats:italic>) is caused by mutations in restricted regions of the genome. Mutations in <jats:styled-content style="fixed-case"><jats:italic>katG</jats:italic></jats:styled-content>, the promoter region of the <jats:styled-content style="fixed-case"><jats:italic>mabA</jats:italic></jats:styled-content><jats:italic>–</jats:italic><jats:styled-content style="fixed-case"><jats:italic>inhA</jats:italic></jats:styled-content> operon, and <jats:styled-content style="fixed-case"><jats:italic>inhA</jats:italic></jats:styled-content> are those most frequently responsible for isoniazid (<jats:styled-content style="fixed-case">INH</jats:styled-content>) resistance. Several <jats:styled-content style="fixed-case">INH</jats:styled-content>‐resistant (<jats:styled-content style="fixed-case">INH<jats:sup>r</jats:sup></jats:styled-content>) <jats:italic><jats:styled-content style="fixed-case">Mtb</jats:styled-content></jats:italic> clinical isolates without mutations in these regions have been described, however, indicating that there are as yet undetermined mechanisms of <jats:styled-content style="fixed-case">INH</jats:styled-content> resistance. We identified the <jats:styled-content style="fixed-case"><jats:italic>mabA</jats:italic></jats:styled-content><jats:sup>g609a</jats:sup> silent mutation in a significant number of <jats:styled-content style="fixed-case">INH<jats:sup>r</jats:sup></jats:styled-content> <jats:italic><jats:styled-content style="fixed-case">Mtb</jats:styled-content></jats:italic> clinical isolates without known <jats:styled-content style="fixed-case">INH</jats:styled-content> resistance mutations. A laboratory strain, <jats:styled-content style="fixed-case">H</jats:styled-content>37<jats:styled-content style="fixed-case">Rv</jats:styled-content>, constructed with <jats:styled-content style="fixed-case"><jats:italic>mabA</jats:italic></jats:styled-content><jats:sup>g609a</jats:sup>, was resistant to <jats:styled-content style="fixed-case">INH</jats:styled-content>. We show here that the <jats:styled-content style="fixed-case"><jats:italic>mabA</jats:italic></jats:styled-content><jats:sup>g609a</jats:sup> mutation resulted in the upregulation of <jats:styled-content style="fixed-case"><jats:italic>inhA</jats:italic></jats:styled-content>, a gene encoding a target for <jats:styled-content style="fixed-case">INH</jats:styled-content>, converting the region adjacent to the mutation into an alternative promoter for <jats:styled-content style="fixed-case"><jats:italic>inhA</jats:italic></jats:styled-content>. The <jats:styled-content style="fixed-case"><jats:italic>mabA</jats:italic></jats:styled-content><jats:sup>g609a</jats:sup> silent mutation results in a novel mechanism of <jats:styled-content style="fixed-case">INH</jats:styled-content> resistance, filling in a missing piece of <jats:styled-content style="fixed-case">INH</jats:styled-content> resistance in <jats:italic><jats:styled-content style="fixed-case">Mtb</jats:styled-content></jats:italic>.</jats:p>

• 出版日期2014-2