DRUGS CONTRADICTING FATTY ACID AND MYCOLIC ACID SYNTHESIS

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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.