The long term objective of the work is to develop novel inhibitors against drug resistant Mycobacteria Tuberculosis. Drug resistant Mycobacteria Tuberculosis poses a significant threat to the health and well being of the world's population. The drug resistant form is particularly hard to treat requiring expensive and prolonged treatment. Death and serious prolonged illness can result from infection even in healthy individuals. Immuno compromised individuals, such as the eldery, those undergoing cancer or transplant therapy and those with diseases which supress immune function, are particularly at risk of becoming infected. Drug resistant M Tuberculosis has been identified as a BAND C priority pathogen by the National Institute of Allergy and Infectious Disease biodefence program. This means there is serious concern that the organism could be weaponised and used against the United States of America or its Allies. To achieve this goal, this project will use protein X-ray crystallography to provide structural data to drive forward rational inhibitor design and synthesis studies.
The specific aims of this project are: 1. To determine the structure of RmlD from M. tuberculosis. 2. Prepare and analyze co-crystals of RmlC, RmlD, and GIf with active compounds prepared by Richard Lee. 3. Determine the structure of farnesyl diphosphate synthase from M. tuberculosis. Determine the structure of this enzyme co-crystallized with inhibitors. 4. Determine the structure of decaprenyl diphosphate synthase from M. tuberculosis. Determine the structure of this enzyme co-crystallized with inhibitors. To realize these aims we will overexpress these proteins in E. coll. The proteins will then be purified to heterogeneity by chromatographic methods. Once pure the protein will be crystallized by incubation with precipitants. Crystals will be examined by X-ray diffraction using in-house sources or synchrotron. Novel structures will be solved with multiple wavelength methods other by molecular replacement methods. Complexes of the proteins with the compounds made by Lee will be formed by either soaking or co-crystallisation. Visual and computer based analysis of these structures will be used to guide computation and synthetic efforts.
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|Scherman, Michael S; North, Elton J; Jones, Victoria et al. (2012) Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability. Bioorg Med Chem 20:3255-62|
|Brown, Joshua R; North, Elton J; Hurdle, Julian G et al. (2011) The structure-activity relationship of urea derivatives as anti-tuberculosis agents. Bioorg Med Chem 19:5585-95|
|Sivendran, Sharmila; Jones, Victoria; Sun, Dianqing et al. (2010) Identification of triazinoindol-benzimidazolones as nanomolar inhibitors of the Mycobacterium tuberculosis enzyme TDP-6-deoxy-d-xylo-4-hexopyranosid-4-ulose 3,5-epimerase (RmlC). Bioorg Med Chem 18:896-908|
|Amin, Anita G; Angala, Shiva K; Chatterjee, Delphi et al. (2009) Rapid screening of inhibitors of Mycobacterium tuberculosis growth using tetrazolium salts. Methods Mol Biol 465:187-201|
|Dhiman, Rakesh K; Mahapatra, Sebabrata; Slayden, Richard A et al. (2009) Menaquinone synthesis is critical for maintaining mycobacterial viability during exponential growth and recovery from non-replicating persistence. Mol Microbiol 72:85-97|
|Sun, Dianqing; Scherman, Michael S; Jones, Victoria et al. (2009) Discovery, synthesis, and biological evaluation of piperidinol analogs with anti-tuberculosis activity. Bioorg Med Chem 17:3588-94|
|Sun, Dianqing; Xu, Hai; Wijerathna, Sanath R et al. (2009) Structure-Based Design, Synthesis, and Evaluation of 2'-(2-Hydroxyethyl)-2'-deoxyadenosine and the 5'-Diphosphate Derivative as Ribonucleotide Reductase Inhibitors. ChemMedChem 4:1649-56|
|Wang, Wenjian; Dong, Changjiang; McNeil, Michael et al. (2008) The structural basis of chain length control in Rv1086. J Mol Biol 381:129-40|
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