This project involves the chemical optimization of both natural and synthetic compounds as potential antituberculars. TBRS chemists perform synthetic modifications of lead molecules either to facilitate understanding of the underlying mechanisms of drug action or to optimize the physiochemical properties of such molecules for preclinical development. 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 called thiolactomycin, and (2) the chemical synthesis of analogs of nitroimidazoles such as PA-824, and (3) the synthesis and evaluation of inhibitors of synthesis of the mycobacterial siderophore, Mycobactin.? ? Project (1) targets mycolic 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. ? ? In collaboration with our collaborators at St Jude's Children's Hospital in Memphis this year we have explored the structure-activity properties of TLM using both parallel solution phase synthesis of analogs and through chemical synthesis of purified natural product. These studies were followed by co-crystallization of two of the semisynthetic analogs with the homologous enzyme from E. coli resulting in significant insight into the nature of the binding site of the 5-position isoprene unit of the natural product. ? ? 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. This project has provided substantial support to the biochemical and genetic studies of the mechanism of action of PA-824 resulting in a significant publication in PNAS listed under 1 Z01 AI000783-09 LIG. In collaboration with scientists at the Novartis Institute for Tropical Diseases, TBRS scientists are engaged in the synthesis and characterization 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.? ? In Project (3) we are evaluating approaches to the inhibition of the biosynthesis of the iron-acquiring siderophore of Mycobacterium tuberculosis, Mycobactin. In collaboration with scientists at the Unvieristy of Minnesota's Center for Drug Design we are testing inhibitors of one of the earliest biosynthetic steps in this biosynthetic pathway. Targetting iron acquisition builds upon a strong historical interest in TBRS in understanding the biosynthesis of this molecule which is required for bacterial growth during infection.
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