Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis
Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis
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DOI：
10.1111/j.1365-2958.2011.07547.x
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发表时间：
2011-03-01
影响因子：
3.6
通讯作者：
Kirikae, Teruo
中科院分区：
文献类型：
--
作者：
Ando, Hiroki;Kitao, Tomoe;Kirikae, Teruo
P>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 KatG（一种过氧化氢酶-过氧化物酶）转化为其活性形式，并攻击 InhA，而 InhA 对于分枝菌酸的合成至关重要。我们对 108 个 INH 耐药 (INHr) 和 51 个 INH 敏感 (INH) 分离株中的furA-katG 和 fabG1-inhA 进行了测序，并在 108 个 INHr 分离株中的 4 个 (4%) 中发现了 FurA-katG 基因间区域的三个突变 (Intg-7a、Inta-10c 和 Intg-12a)，以及带有氨基的 FurAc41t 突变。 18 个 INHR 分离株 (17%) 中的酸取代。在测试的 51 个 INH 分离株中均未发现这些突变。我们在同基因菌株中重建了这些突变，以确定它们是否赋予 INH 抗性。我们发现furA-katG基因间区域的Intg-7a、Inta-10c和Intg-12a单突变降低了katG表达并赋予INH耐药性。相比之下，furAc41t 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，并且furA-katG基因间区域的突变在这种耐药机制中发挥作用。
P>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 (INHr) and 51 INH-susceptible (INHs) isolates, and found three mutations in the furA-katG intergenic region (Intg-7a, Inta-10c and Intg-12a) in four of 108 INHr isolates (4%), and the furAc41t mutation with an amino acid substitution in 18 INHr isolates (17%). These mutations were not found in any of 51 INHs isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Intg-7a, Inta-10c and Intg-12a single mutations in the furA-katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furAc41t 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.