National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku, Tokyo 162-8655, Japan.
Mol Microbiol. 2011 Mar;79(6):1615-28. doi: 10.1111/j.1365-2958.2011.07547.x. Epub 2011 Feb 10.
Isoniazid (INH) is a key agent in the treatment of tuberculosis. In Mycobacterium tuberculosis, INH is converted to its active form by KatG, a catalase-peroxidase, and attacks InhA, which is essential for the synthesis of mycolic acids. We sequenced furA-katG and fabG1-inhA in 108 INH-resistant (INH(r) ) and 51 INH-susceptible (INH(s) ) isolates, and found three mutations in the furA-katG intergenic region (Int(g-7a) , Int(a-10c) and Int(g-12a) ) in four of 108 INH(r) isolates (4%), and the furA(c41t) mutation with an amino acid substitution in 18 INH(r) isolates (17%). These mutations were not found in any of 51 INH(s) isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Int(g-7a) , Int(a-10c) and Int(g-12a) single mutations in the furA-katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furA(c41t) mutation was not sufficient to confer INH resistance. These results suggested that downregulation of katG is a mechanism of INH resistance in M. tuberculosis and that mutations in the furA-katG intergenic region play a role in this resistance mechanism.
异烟肼（INH）是治疗结核病的关键药物。在结核分枝杆菌中，INH 被过氧化氢酶-过氧化物酶 KatG 转化为其活性形式，并攻击 InhA，后者对于合成分枝菌酸至关重要。我们对 108 株 INH 耐药（INH(r)）和 51 株 INH 敏感（INH(s)）分离株中的 furA-katG 和 fabG1-inhA 进行了测序，在 108 株 INH(r) 分离株中的 4 株（4%）中发现了 furA-katG 基因间区（Int(g-7a)、Int(a-10c)和 Int(g-12a)）中的三个突变，以及 18 株 INH(r) 分离株中的 furA(c41t)突变，该突变导致一个氨基酸取代。在测试的 51 株 INH(s)分离株中均未发现这些突变。我们在同源株中重建了这些突变，以确定它们是否赋予 INH 耐药性。我们发现 furA-katG 基因间区中的 Int(g-7a)、Int(a-10c)和 Int(g-12a) 单个突变降低了 katG 的表达并赋予了 INH 耐药性。相比之下，furA(c41t)突变不足以赋予 INH 耐药性。这些结果表明，katG 的下调是结核分枝杆菌中 INH 耐药的一种机制，而 furA-katG 基因间区的突变在这种耐药机制中发挥作用。
