The complex cell wall of these gram-positive actinomycetes is their most characteristic feature and its biosynthesis is the target of some of the most effective antimycobacterial agents. A better understanding of the biochemical transformations used in cell wall elaboration will allow us to design novel interventions through the use of the tools of rational drug design and combinatorial chemistry. This project has focussed on understanding the biosynthetic relationships of various cell wall constituents through the use of the classical techniques of protein purification and analysis as well as genetic manipulation of various mycobacterial species. Many of these studies have involved mycolic acids, complex alpha-branched, beta-hydroxy fatty acids that are unique to mycobacteria which are heavily modified by a variety of functional groups.Mycolic acids are biosynthetically produced through an extension of normal fatty acid metabolism. In mycobacteria this is initiated by a """"""""eukaryotic""""""""-like Type I fatty acid synthase, a large multifunctional enzyme that produces primarily short-chain (16-24 carbons) fatty acids that are then substrates for a second fatty acid synthase system that is more typically associated with bacteria. This Type II system appears to be the molecular target for isoniazid as well as other inhibitors such as triclosan and thiolactomycin. Understanding the relationships between these inhibitors has provided us with a valuable tool in elucidating the fundamental biochemistry underlying production of these exceptional lipids. Examining components of the fatty acid synthase system from patients that harbor drug resistant bacteria has allowed us to establish that regulating these components carefully plays a critical role in the bacterial response to (and resistance to) isoniazid.
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