MOLECULAR BIOLOGY OF UNIQUE WALL LIPIDS OF MYCOBACTERIA

结核分枝杆菌和相关的致病分枝杆菌 它们的细胞壁中含有大量独特的脂类。其中一些独一无二的 脂类是致病分枝杆菌的表面抗原，可以 有助于识别、诊断和治疗。这些脂类 构成屏障，使细菌能够抵抗自然的 防御宿主，抵抗抗微生物药物，并帮助在体内繁殖 主持人。目前使用的抗分支杆菌药物是有针对性的 抗真菌酸的生物合成，一类独特的 脂类。对这些药物的耐药性已经成为一个主要问题。 其他独特脂质的生物合成可能成为新的目标 抗分枝杆菌药物。多甲基支链超长链脂肪 酸，如真菌酸和β-二醇，邻苯二甲酸乙二醇酯和 这些酸被酯化成的酚硫醇是独一无二的 慢生病原菌细胞壁脂类成分的研究 分枝杆菌。即使是分枝杆菌的脂肪酸合成酶也有 独特的催化脂肪酸从头合成和 链延长以产生超长链酸前体 独特的分枝杆菌脂类。对生物化学和生物化学的理解 这些独特的脂类的分子生物学可以帮助设计新药。 为此，我们建议追求以下具体目标：1. 确定分枝菌酸是如何从分枝菌酸中排出的 合成酶在细胞壁结构中生成邻苯二甲酸甘油酯和酚硫甘油酯。 2.干扰分枝杆菌酸合成酶基因，并测定 对细胞壁结构的敏感性和致病力的影响。3. 确定分枝杆菌酸合成酶中负责 甲基丙二酰辅酶A的选择性掺入以产生多个 甲基分枝细胞壁脂。4.阐明途径、酶学 和参与邻苯三酚生物合成的基因的结构和 酚硫醇。5.阐明两者之间的结构关系 分枝杆菌酸合成酶和脂肪酸合成酶的研究 分枝杆菌脂肪酸独特功能的分子基础 合成酶催化从头合成脂肪酸和链 伸长率。 有可能拟议中对独特过程的解释 致病分枝杆菌可能导致新的方法来识别和 诊断每年导致数百万人死亡的分枝杆菌感染 并与结核病和其他分枝杆菌的卷土重来作斗争 美国艾滋病患者的感染情况。

Mycobacterium tuberculosis and related pathogenic mycobacteria have large amounts of unique lipids in their cell walls. Some of these unique lipids are surface antigens of the pathogenic mycobacteria and can be useful in identification, diagnosis and treatment. These lipids constitute barriers that allow the bacteria to resist the natural defenses of the host, resist antimicrobial drugs and help multiply within the host. The antimycobacterial drugs currently in use are directed against the biosynthesis of mycolic acids, one class of the unique lipids. Resistance against these drugs has become a major problem. Biosynthesis of other unique lipids could be suitable targets for new antimycobacterial drugs. Multiple methyl branched very long chain fatty acids such as mycocerosic acids and the beta-diols, phthiocerol and phenolphthiocerol, to which these acids are esterified, are unique constituents of the cell wall lipids of the slow growing pathogenic mycobacteria. Even the fatty acid synthase of mycobacteria has the unique ability to catalyze both de novo synthesis of fatty acids and chain elongation to generate the very long chain acid precursors of the unique mycobacterial lipids. Understanding of the biochemistry and molecular biology of these unique lipids could help design new drugs. To this end, we propose to pursue the following specific objectives: 1. Determine how mycocerosic acids are channeled from mycocerosic acid synthase to phthiocerol and phenolthiocerol in the cell wall structure. 2. Disrupt the mycocerosic acid synthase gene and determine the consequences on the cell wall structure susceptibility and virulence. 3. Determine the domains in mycocerosic acid synthase responsible for the selective incorporation of methylmalonyl-CoA to generate the multiple methyl branched cell wall lipids. 4. Elucidate the pathway, enzymology and structure of the gene involved in the biosynthesis of phthiocerol and phenolphthiocerol. 5. Elucidate the structural relationship between mycocerosic acid synthase and the fatty acid synthase and elucidate the molecular basis of the unique capability of mycobacterial fatty acid synthase to catalyze both de novo fatty acid synthesis and chain elongation. It is possible that the proposed elucidation of unique processes in pathogenic mycobacteria could lead to novel methods to identify and diagnose mycobacterial infections that kill millions of people annually and to combat the resurgence of tuberculosis and other mycobacterial infections in AIDS patients in the United States.