The Arabinosyltransferase EmbC Is Inhibited by Ethambutol in Mycobacterium tuberculosis
The Arabinosyltransferase EmbC Is Inhibited by Ethambutol in Mycobacterium tuberculosis
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DOI：
10.1128/aac.00162-09
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发表时间：
2009-10-01
影响因子：
4.9
通讯作者：
Parish, T.
中科院分区：
文献类型：
--
作者：
Goude, R.;Amin, A. G.;Parish, T.
乙胺丁醇（Ethambutol，EMB）是一种抗结核药物，广泛用于治疗结核分枝杆菌引起的结核病。EMB靶向细胞壁的生物合成，抑制阿拉伯半乳聚糖和脂阿拉伯甘露聚糖（LAM）的合成，并被认为通过抑制三种阿拉伯糖基转移酶发挥作用：EmbA、EmbB和EmbC。EmbA和EmbB是合成阿拉伯半乳聚糖所必需的，并且至少一种酶（M.结核分枝杆菌（M. tuberculosis，M.结核EmbC（Mt）对M.结核病，但参与合成LAM。我们发现，EmbCMt中的突变降低了其阿拉伯糖基转移酶活性，导致对EMB的敏感性增加，并在M中产生较小的LAM种类。结核在M.结核分枝杆菌（M. tuberculosis）对EMB的耐药率较高，但过表达的耻垢分枝杆菌EmbC（EmbC（Ms））导致M.结核野生型M.结核菌株与EMB导致LAM合成的抑制，导致较小种类的LAM的产生。与此相反，没有变化的LAM生产中看到EMB耐药菌株。EmbB（Ms）在M.结核病也导致EMB耐药，但水平低于EmbC（Ms）。EmbA（Mt）在M.结核病对EMB耐药无影响。因此，在EmbC活性和EMB抗性之间，以及在EmbC活性和所产生的LAM种类的大小之间存在直接相关性，证实了EmbC是EMB作用的细胞靶标之一。
Ethambutol (EMB) is an antimycobacterial drug used extensively for the treatment of tuberculosis caused by Mycobacterium tuberculosis. EMB targets the biosynthesis of the cell wall, inhibiting the synthesis of both arabinogalactan and lipoarabinomannan ( LAM), and is assumed to act via inhibition of three arabinosyl-transferases: EmbA, EmbB, and EmbC. EmbA and EmbB are required for the synthesis of arabinogalactan, and at least one enzyme ( M. tuberculosis EmbA [EmbA(Mt)]) is essential in M. tuberculosis. EmbC(Mt) is also essential for the viability of M. tuberculosis but is involved in the synthesis of LAM. We show that mutations in EmbCMt that reduce its arabinosyltransferase activity result in increased sensitivity to EMB and the production of smaller LAM species in M. tuberculosis. Overexpression of EmbC(Mt) was not tolerated in M. tuberculosis, but overexpression of Mycobacterium smegmatis EmbC (EmbC(Ms)) led to EMB resistance and the production of larger LAM species in M. tuberculosis. Treatment of wild-type M. tuberculosis strains with EMB led to inhibition of LAM synthesis, resulting in the production of smaller species of LAM. In contrast, no change in LAM production was seen in EMB-resistant strains. Overexpression of EmbB(Ms) in M. tuberculosis also resulted in EMB resistance, but at a lower level than that caused by EmbC(Ms). Overexpression of EmbA(Mt) in M. tuberculosis had no effect on EMB resistance. Thus, there is a direct correlation between EmbC activity and EMB resistance, as well as between EmbC activity and the size of the LAM species produced, confirming that EmbC is one of the cellular targets of EMB action.