DRUGS CONTRADICTING FATTY ACID AND MYCOLIC ACID SYNTHESIS

项目1的重点是脂肪酸合成、霉菌酸合成和细胞壁沉积，这是CSU和SmithKline Beecham(SB)共同的主题。该项目的一个主要目的是促进SB参与结核病药物发现倡议，这些主题与SB强调的作为药物发现目标的几种革兰氏阳性细菌的脂肪酸合成是一致的。针对SB的具体目标1解决了高通量筛选(HTS)、细胞毒性、疗效研究和药物化学在SKF系列SM化合物中的应用，其中一些化合物显示出特殊的前景。此外，结核分枝杆菌特有的Fas I、Fas II和Mycolylsynthase将被纳入SB的主流三阶段抗感染药物发现计划。特定目标2(在CSU)继续令人惊讶地观察到，异氧基的主要作用可能不是对真菌酸，而是对油酸(因此，结核硬脂酸)的合成，因此去饱和酶(DesA1/A2)是许多硫脲的主要靶标。具体目标3(在CSU和德克萨斯A&M)在全面应用高温超导之前，从遗传、结构和酶分析的角度解决了霉菌酸通过膜转移和在代谢最终产品中的沉积问题。

Project 1 focuses on fatty acid synthesis and mycolic acid synthesis and cell wall deposition as the shared theme between CSU and SmithKline Beecham (SB). A primary purpose of the Project is to facilitate the involvement of SB in the tuberculosis drug discovery initiative, and these themes are in conformity with SB's emphasis on fatty acid synthesis in several Gram-positive bacteria as the target for drug discovery. Specific Aim 1 at SB addresses the application of high throughput screens (HTS), cytotoxicity, and efficacy studies and medicinal chemistry to the SKF series of SM compounds, some of which show exceptional promise. Also, the characteristic FAS I, FAS II and mycolylsynthase of M. tuberculosis will be incorporated into SB's mainstream three-phase anti-infectives drug discovery program. Specific Aim 2 (at CSU) continues with the surprising observation that the primary effect of isoxyl is probably not on mycolic acid but on oleic acid (and, hence, tuberculostearic acid) synthesis and, hence the desaturases (DesA1/A2) are the primary targets of a host of thioureas. Specific Aim 3 (at CSU and Texas A&M) addresses mycolic acid transfer through membrane and deposition in metabolic end-products, from genetic, structural and enzymatic-assay perspectives prior to the application of full-scale HTS.