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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Molecular investigation of resistance to the antituberculous drug ethionamide in multidrug-resistant clinical isolates of Mycobacterium tuberculosis.
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Molecular investigation of resistance to the antituberculous drug ethionamide in multidrug-resistant clinical isolates of Mycobacterium tuberculosis.

机译：结核分枝杆菌多药耐药临床分离株对抗结核药乙硫酰胺耐药性的分子研究。

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Ethionamide (ETH) needs to be activated by the mono-oxygenase EthA, which is regulated by EthR, in order to be active against Mycobacterium tuberculosis. The activated drug targets the enzyme InhA, which is involved in cell wall biosynthesis. Resistance to ETH has been reported to result from various mechanisms, including mutations altering EthA/EthR, InhA and its promoter, the NADH dehydrogenase encoded by ndh, and the MshA enzyme, involved in mycothiol biosynthesis. We searched for such mutations in 87 clinical isolates: 47 ETH-resistant (ETH(r)) isolates, 24 ETH-susceptible (ETH(s)) isolates, and 16 isolates susceptible to ETH but displaying an intermediate proportion of resistant cells (ETH(Sip); defined as >/=1% but <10% resistant cells). In 81% (38/47) of the ETH(r) isolates, we found mutations in ethA, ethR, or inhA or its promoter, which mostly corresponded to new alterations in ethA and ethR. The 9 ETH(r) isolates without a mutation in these three genes (9/47, 19%) had no mutation in ndh, and a single isolate had a mutation in mshA. Of the 16 ETH(Sip) isolates, 7 had a mutation in ethA, 8 had no detectable mutation, and 1 had a mutation in mshA. Finally, of the 24 ETH(s) isolates, 23 had no mutation in the studied genes and 1 displayed a yet unknown mutation in the inhA promoter. Globally, the mechanism of resistance to ETH remained unknown for 19% of the ETH(r) isolates, highlighting the complexity of the mechanisms of ETH resistance in M. tuberculosis.
机译：为了对结核分枝杆菌有活性，乙酰胺（ETH）需要被EthR调节的单加氧酶EthA激活。激活的药物靶向酶InhA，该酶参与细胞壁生物合成。据报道，对ETH的抗性是由多种机制引起的，包括改变EthA / EthR，InhA及其启动子的突变，由ndh编码的NADH脱氢酶和参与甲硫醇生物合成的MshA酶。我们在87个临床分离株中搜索了此类突变：47个ETH耐药（ETH（r））分离株，24个ETH易感（ETH（s））分离株和16个对ETH敏感但表现出中等比例的耐药细胞（ETH）分离株（Sip）;定义为> / = 1％但<10％的抗性细胞）。在81％（38/47）的ETH（r）分离株中，我们发现ethA，ethR或inhA或其启动子中的突变，主要与ethA和ethR的新变化相对应。在这三个基因中没有突变的9个ETH（r）分离株（9 / 47，19％）在ndh中没有突变，单个分离株在mshA中有突变。在16个ETH（Sip）分离株中，有7个在ethA中发生了突变，有8个没有可检测到的突变，有1个在mshA中有了突变。最后，在24个ETH分离株中，有23个在研究的基因中没有突变，而1个在inhA启动子中显示了未知的突变。在全球范围内，对于19％的ETH（r）分离株，对ETH的抗药性机制仍然未知，这突出了结核分枝杆菌对ETH的抗药性机制的复杂性。

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