Development Of New Chemotherapeutics For Tuberculosis

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Abstract

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. Currently this project focusses on two areas: (1) the chemical synthesis of derivatives of a natural product that targets an enzyme involved in the biosynthesis of the mycobacterial cell wall, and (2) the chemical synthesis of analogs of nitroimidazoles such as PA-824 as drug development candidates. Project (1) targets ycolic acids which are 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. Thiolactomycin is a low molecular weight natural product isolated from a soil Nocardia species that specifically inhibits one component of the bacterial Type II fatty acid synthase system. Although it is a modest inhibitor against most bacteria it has shown in vivo activity in various experimental infections of animals. Our collaborators at St Jude's Children's Hospital in Memphis have solved the crystal structure of thiolactomycin in complex with its target, the beta-ketoacyl ACP synthase, from E coli. In collaboration with GlaxoSmithKline we are currently synthesizing and testing derivatives of thiolactomycin to produce analogs with improved potency against tuberculosis. Using the co-crystal of thiolactomycin with its target as a guide, we are attempting to make rational improvements in the structure which should improve binding to the active site of this enzyme. In Project (2) we are synthesizing analogs of nitroimiadazooxazines and nitorimidazooxazoles related to PA-824. PA-824 is currently undergoing preclinical development in advance of Phase I studies in humans for the treatment of tuberculosis. PA-824 faces some serious obstacles as a drug candidate including limited solubility, difficult synthetic method and unknown mechanism of action. In collaboration with scientists at the Novartis Institute for Tropical Diseases, TBRS scientists are engaged in the synthesis of analogs of these compounds designed to either elucidate details of the mechanism of action or to improve the characteristics of this class of compounds as drug candidates.