GENETIC ANALYSIS OF MYCOLIC ACID SYNTHESIS

分枝杆菌细胞壁的独特结构是由于新的 共价键合的分枝菌酸的排列及其特征 阿拉伯半乳聚糖-肽聚糖复合物。 毫无疑问，生物合成 这种细胞壁基质的生物合成途径将高度涉及 专门的酶和酶复合物，可用于 开发新的抗分枝杆菌药物。 迫切需要发展 控制结核病的新的和更有效的化学治疗剂， 导致我们目前努力定义关键细胞壁的生物合成 产品. 在合理药物设计的最独特的目标中， 抗结核和非典型分枝杆菌病的细胞壁 分枝菌酸盐-α-烷基、β-羟基长链（C80）脂肪酸。 的 对它们的生物合成的研究，可能涉及专门的伸长， Claisen冷凝和“运输机”（项目1）将得到补充 通过鉴定基因、产生同基因突变体和提供 用于SAR研究的重组酶。 我们的关键观察是， 一级分枝菌酰转移酶是众所周知的抗原85，α-抗原 复杂，编码关键靶点的基因因此是已知的，并且已经成熟， 构建“敲除”突变体。 FAS-I最近的可用性， -II酶，允许通过反向遗传学定位它们的基因， 也被操纵。 已重组M.结核分枝杆菌一直是 在M中表示。为遗传学定义提供了现成的方法 f是结核杆菌最具特征的表型， 在我们的工业合作伙伴眼中， 新药开发的重点。

The unique architecture of the mycobacterial cell wall is due to the novel arrangement of the covalently bound mycolic acids and the characteristic arabinogalactan-peptidoglycan complex. Undoubtedly, the biosynthetic pathways for the biosynthesis of this cell wall matrix will involve highly specialized enzymes and enzyme complexes that may be exploited for the development of new anti-mycobacterial drugs. The urgent need to develop new and more effective chemotherapeutic agents to control tuberculosis has lead to our current endeavors in defining the biosynthesis of key cell wall products. Among the most distinctive targets for rational drug design against tuberculosis and atypical mycobacterioses are the cell wall mycolates - alpha-alkyl, beta-hydroxy long chain (C80) fatty acids. The study of their biosynthesis, presumably involving specialized elongation, Claisen condensation and "transporters; (Project 1), will be complemented by identification of genes, generation of isogeneic mutants, and provision of recombinant enzymes for SAR studies. With our key observation that a primary mycolyltransferase is the well known antigen 85, alpha-antigen complex, the genes encoding a key target are thus known and are ripe for construction of "knock-out" mutants. The recent availability of FAS-I and -II enzymes, allows for their genes to be located by reverse genetics and also manipulated. Already recombinant M. tuberculosis mycolates have been expressed in M. smegmatis providing a ready means for genetic definition f the most characteristic phenotype of the tubercle bacillus, and also the site of effective drugs, and, in the eyes of our industrial partners, a prime focus for new drug development.