National Reference Centre for Mycobacteria, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.
Antimicrob Agents Chemother. 2011 Jan;55(1):355-60. doi: 10.1128/AAC.01030-10. Epub 2010 Oct 25.
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.
乙硫异烟胺（ETH）需要被单加氧酶 EthA 激活，EthA 受 EthR 调控，才能对结核分枝杆菌发挥作用。活性药物靶向参与细胞壁生物合成的酶 InhA。已报道对 ETH 的耐药性是由多种机制引起的，包括改变 EthA/EthR、InhA 及其启动子、编码 NADH 脱氢酶的 ndh 和参与麦角硫因生物合成的 MshA 酶的突变。我们在 87 株临床分离株中寻找这些突变：47 株乙硫异烟胺耐药（ETH(r)）分离株、24 株乙硫异烟胺敏感（ETH(s)）分离株和 16 株对 ETH 敏感但表现出中间比例耐药细胞的分离株（ETH(Sip)；定义为≥1%但<10%耐药细胞）。在 81%（38/47）的 ETH(r)分离株中，我们发现 ethA、ethR 或 inhA 或其启动子发生突变，这些突变主要对应于 ethA 和 ethR 的新改变。这三个基因无突变的 9 株 ETH(r)分离株（9/47，19%）在 ndh 中没有突变，一株分离株在 mshA 中有突变。在 16 株 ETH(Sip)分离株中，7 株有 ethA 突变，8 株未检测到突变，1 株有 mshA 突变。最后，在 24 株 ETH(s)分离株中，23 株未在研究基因中发生突变，1 株在 inhA 启动子中显示未知突变。总体而言，19%的 ETH(r)分离株对 ETH 的耐药机制仍然未知，这突显了结核分枝杆菌中 ETH 耐药机制的复杂性。
