A purpose of NIH Notice NOT-AI-02-023 is to expedite research leading to the treatment of MDR-TB, a potential bioterrorism agent. New chemotherapies based on different targets than the present TB drugs are needed, but there is a paucity of the required leads ready for clinical trials. In response to this lack of required leads, it is proposed to develop new leads active against MDR-TB and effective in mice by developing inhibitors of several essential cell wall synthetic enzymes not targeted by current drugs. Compounds that inhibit three different cell wall synthetic enzymes (some of which also inhibit the growth of TB) have been identified by screening a chemical library with microtiter plate based enzyme assays. These and similarly identified hits will be refined into highly effective enzyme inhibitors also active against MDR-TB using a """"""""compound refinement"""""""" cycle. The cycle begins with the """"""""compound development group"""""""" doing X-ray crystallography studies of the targeted enzymes (especially enzymes with bond inhibitors), proceeding to molecular modeling to design new inhibitors and finally synthesizing a group of compounds based on this modeling and also incorporating chemical diversity. Then the """"""""compound analysis group"""""""" determines efficacy of enzyme inhibition, MIC values on a panel of MDR-TB isolates, in vitro cell toxicity, and as warranted, toxicity in mice, efficacy in an interferon gamma knock out mouse, basic pharmacokinetics, and efficacy in a standard mouse model. The data from the compound analysis group is relayed to the compound development group so that a new round of further refined compounds can be prepared. The cycle is continued for each class of inhibitors until compounds with the desired properties emerge or it is determined that a particular class of compounds is unlikely to be yield new drugs. The cycle is presently ready to begin with inhibitors of three essential enzymes; in addition we will develop microtiter plate assays and screen chemical libraries for hits for four additional essential cell wall biosynthetic enzymes which will then enter the refinement cycle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI057836-05
Application #
7442228
Study Section
Special Emphasis Panel (ZAI1-GLM-M (J1))
Program Officer
Lacourciere, Karen A
Project Start
2004-06-15
Project End
2011-03-31
Budget Start
2008-06-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$906,176
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
North, E Jeffrey; Scherman, Michael S; Bruhn, David F et al. (2013) Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties. Bioorg Med Chem 21:2587-99
Grzegorzewicz, Anna E; Pham, Ha; Gundi, Vijay A K B et al. (2012) Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat Chem Biol 8:334-41
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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