Mycolic acid methyltransferase, MmaA4, is necessary for thiacetazone susceptibility in Mycobacterium tuberculosis
Mycolic acid methyltransferase, MmaA4, is necessary for thiacetazone susceptibility in Mycobacterium tuberculosis
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DOI：
10.1111/j.1365-2958.2009.06604.x
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发表时间：
2009-03-01
影响因子：
3.6
通讯作者：
Kremer, Laurent
中科院分区：
文献类型：
--
作者：
Alahari, Anuradha;Alibaud, Laeticia;Kremer, Laurent
结核分枝杆菌对二线抗结核药物噻醋酮 (TAC) 的敏感性需要单加氧酶 EthA 的激活。在这里，我们报告了牛分枝杆菌 BCG 中自发突变体的分离，这些突变体对 TAC 高度耐药，但携带功能性 EthA。出乎意料的是，大多数 TAC 抗性突变体缺乏酮分支菌酸，酮分支菌酸是与细胞壁相关的长链脂肪酸，对结核病的病理生理学有显着贡献。可以预见，上述突变体的致病突变位于编码甲基转移酶 MmaA4 的基因中，该基因是合成酮-和甲氧基-分枝菌酸所必需的。 BCG 突变体的耐药表型在结核分枝杆菌 CDC1551 的 mmaA4 突变体中重现，但在 mmaA3 无效突变体中未重现。通过与功能性 mmaA4 基因互补可以恢复对 TAC 的敏感性。有趣的是，MmaA4 在牛分枝杆菌 BCG 中的过度表达使其更容易受到 TAC 的影响。我们通过 EthA 和 MmaA4 的协调作用，为抗结核药物的激活提供了新的机制见解。这项研究首次证明了与氧化分枝杆菌酸合成相关的酶参与结核分枝杆菌药物激活过程，并强调了分枝杆菌酸合成、药物激活和分枝杆菌毒力之间的相互作用。
Susceptibility of Mycobacterium tuberculosis to the second-line antitubercular drug thiacetazone (TAC) requires activation by the monoxygenase, EthA. Here, we report isolation of spontaneous mutants in Mycobacterium bovis BCG that are highly resistant to TAC, but carry a functional EthA. Unexpectedly, a majority of the TAC-resistant mutants lacked keto-mycolic acids, which are long-chain fatty acids associated with the cell wall and which contribute significantly to the physiopathology of tuberculosis. Predictably, causative mutations in the above mutants were in the gene encoding methyltransferase MmaA4, which is required for synthesis of keto- and methoxy-mycolic acids. Drug-resistant phenotype of the BCG mutants was reproduced in a mmaA4, but not in a mmaA3 null mutant of M. tuberculosis CDC1551. Susceptibility to TAC could be restored by complementation with a functional mmaA4 gene. Interestingly, overexpression of MmaA4 in M. bovis BCG made it more susceptible to TAC. We provide novel mechanistic insights into antitubercular drug activation by co-ordinated actions of EthA and MmaA4. This study is the first demonstration of the participation of an enzyme linked to the synthesis of oxygenated mycolates in a drug activation process in M. tuberculosis, and highlights the interplay between mycolic acid synthesis, drug activation and mycobacterial virulence.