The cell-wall core of Mycobacterium tuberculosis in the context of drug discovery
The cell-wall core of Mycobacterium tuberculosis in the context of drug discovery
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DOI：
10.2174/156802607780059763
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发表时间：
2007-01-01
影响因子：
3.4
通讯作者：
Crick, Dean C.
中科院分区：
文献类型：
--
作者：
Brennan, Patrick J.;Crick, Dean C.
目前对结核分枝杆菌整个细胞壁结构的理解相当于一个“核心”模板，该模板由具有磷酸二酯键的肽聚糖组成，通过连接体二糖连接到线性D-半乳呋喃上，而线性D-半乳呋喃上又连接了几条高度支化的D-阿拉伯呋喃链。细胞壁分枝菌酸通过酯与D-阿拉伯聚糖的大部分非还原末端连接。分枝菌酸垂直于膜平面，提供了一个真正特殊的脂质屏障，负责许多生理和疾病诱导方面的M。结核嵌入该环境中的是邻苯二甲酸二霉菌蜡酸酯、脐带因子或二霉菌酰海藻糖、硫脂、磷脂酰肌醇甘露糖苷和相关的脂甘露聚糖和脂阿拉伯甘露聚糖等，结核病的发病机制中起主要作用的病原体。与辅助脂质不同，细胞壁核心的生物合成被认为是细菌生存力和完整性所必需的，现在对替代药物的迫切需求推动了对细胞壁核心的生物合成的兴趣，以对抗耐药结核病。以类似于脂质I和11在肽聚糖形成中的作用的方式，整个阿拉伯半乳聚糖的合成是通过将活化的糖转移到十异戊烯基磷酸盐来启动的，产生接头二糖，然后逐步延长半乳聚糖和阿拉伯聚糖，显然一次一种糖。这些聚合事件的遗传学和酶学尚未得到很好的定义，也没有最后的步骤，即分枝菌酸的连接和连接肽聚糖。然而，已知的细胞壁核心合成的早期事件在新的抗结核药物开发方面引起了兴趣。
Present-day understanding of the architecture of the entire cell-wall of Mycobacterium tuberculosis amounts to a "core" template comprised of peptidoglycan with phosphodiester linkage, via a linker disaccharide, to a linear D-galactofuran, to which, in turn, are attached several strands of a highly branched D-arabinofuran. The cell-wall mycolic acids are linked via an ester to the majority of the non-reducing termini of the D-arabinan. The mycolic acids are oriented perpendicular to the plane of the membrane and provide a truly special lipid barrier responsible for many of the physiological and disease-inducing aspects of M. tuberculosis. Intercalated within this environment are the phthiocerol dimycocerosates, cord factor or dimycolyltrehalose, sulfolipids, phosphatidylinositol mannosides and the related lipomannan and lipoarabinomannan, etc., agents responsible for much of the pathogenesis of tuberculosis. Interest in the biosynthesis of the cell-wall core, regarded, unlike the ancillary lipids, as essential to bacterial viability and integrity, is now driven by the pressing need for alternative drugs to counteract drug-resistant tuberculosis. In a manner analogous to the roles of lipid I and 11 in peptidglycan formation, synthesis of the entire arabinogalactan is initiated by transferring activated sugars to decaprenyl-phosphate, giving rise to the linker disaccharide, followed by stepwise elongation of the galactan, and the arabinan, apparently one sugar at a time. The genetics and enzymology of these polymerization events have not been well defined, nor have the final steps, namely the attachment of mycolic acids and ligation to peptidoglycan. However, what is known of the earlier events in cell-wall core synthesis has attracted interest in terms of new anti-tuberculosis drug development.