Abstract
Tuberculosis (TB) infects one-third of the world population. Despite 50 years of available drug treatments, TB continues to increase at a significant rate. The failure to control TB stems in part from the expense of delivering treatment to infected individuals and from complex treatment regimens. Incomplete treatment has fueled the emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis (Mtb). Reducing non-compliance by reducing the duration of chemotherapy will have a great impact on TB control. The development of new drugs that either kill persisting organisms, inhibit bacilli from entering the persistent phase, or convert the persistent bacilli into actively growing cells susceptible to our current drugs will have a positive effect. We are taking a multidisciplinary approach that will identify and characterize new drug targets that are essential for persistent Mtb. Targets are exposed to a battery of analyses including microarray experiments, bioinformatics, and genetic techniques to prioritize potential drug targets from Mtb for structural analysis. Our core structural genomics pipeline works with the individual laboratories to produce diffraction quality crystals of targeted proteins, and structural analysis will be completed by the individual laboratories. We also have capabilities for functional analysis and the virtual ligand screening to identify novel inhibitors for target validation. Our overarching goals are to increase the knowledge of Mtb pathogenesis using the TB research community to drive structural genomics, particularly related to persistence, develop a central repository for TB research reagents, and discover chemical inhibitors of drug targets for future development of lead compounds.
Keywords: free-interface diffusion screening chip, Virtual screening, ATP-phosphoribosyl transferase, Mycolic acid, Pantothenate Synthetase, Arginine Metabolism
Infectious Disorders - Drug Targets
Title: High Throughput Crystallography of TB Drug Targets
Volume: 7 Issue: 2
Author(s): T.R. Ioerger, J.C. Sacchettini, S. Wang, F.Wang, T.C. Terwilliger, B.W. Segelke, R. Sankaranarayanan, J.S. Lott, I. Krieger, C. Kim, M.N.G.James, W.R. Jacobs, A.C. Murillo, L. W. Hung, C.W. Goulding, C.R. Garen, D. Eisenberg, Yoon Song Cho, M.M. Cherney, L.T. Cherney, J.M. Berger, E.N. Baker, T. Alber and H.Y. Li
Affiliation:
Keywords: free-interface diffusion screening chip, Virtual screening, ATP-phosphoribosyl transferase, Mycolic acid, Pantothenate Synthetase, Arginine Metabolism
Abstract: Tuberculosis (TB) infects one-third of the world population. Despite 50 years of available drug treatments, TB continues to increase at a significant rate. The failure to control TB stems in part from the expense of delivering treatment to infected individuals and from complex treatment regimens. Incomplete treatment has fueled the emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis (Mtb). Reducing non-compliance by reducing the duration of chemotherapy will have a great impact on TB control. The development of new drugs that either kill persisting organisms, inhibit bacilli from entering the persistent phase, or convert the persistent bacilli into actively growing cells susceptible to our current drugs will have a positive effect. We are taking a multidisciplinary approach that will identify and characterize new drug targets that are essential for persistent Mtb. Targets are exposed to a battery of analyses including microarray experiments, bioinformatics, and genetic techniques to prioritize potential drug targets from Mtb for structural analysis. Our core structural genomics pipeline works with the individual laboratories to produce diffraction quality crystals of targeted proteins, and structural analysis will be completed by the individual laboratories. We also have capabilities for functional analysis and the virtual ligand screening to identify novel inhibitors for target validation. Our overarching goals are to increase the knowledge of Mtb pathogenesis using the TB research community to drive structural genomics, particularly related to persistence, develop a central repository for TB research reagents, and discover chemical inhibitors of drug targets for future development of lead compounds.
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T.R. Ioerger , J.C. Sacchettini , S. Wang , F.Wang , T.C. Terwilliger , B.W. Segelke , R. Sankaranarayanan , J.S. Lott , I. Krieger , C. Kim , M.N.G.James , W.R. Jacobs , A.C. Murillo , L. W. Hung , C.W. Goulding , C.R. Garen , D. Eisenberg , Yoon Song Cho , M.M. Cherney , L.T. Cherney , J.M. Berger , E.N. Baker , T. Alber and H.Y. Li , High Throughput Crystallography of TB Drug Targets, Infectious Disorders - Drug Targets 2007; 7 (2) . https://dx.doi.org/10.2174/187152607781001853
DOI https://dx.doi.org/10.2174/187152607781001853 |
Print ISSN 1871-5265 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3989 |
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New Frontiers in Infectious Disease Research: Small-Molecule Probes and Biomarker Identification
The biological relevance of small-molecule chemical probes targeting a disease model is crucial in the early stages of drug discovery. The integration of omics technologies such as genomics, proteomics, metabolomics, immunomic, and cellular levels has greatly enhanced the ability to identify novel biomarkers and understand the complex interactions between pathogens ...read more
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