Multi-drug resistant tuberculosis (MDR-TB) is an emerging infectious disease threat classified as a category C priority pathogen by NIH. Currently, a series of compounds have been designed and synthesized that are nanomolar inhibitors of the M. tuberculosis (MTB) enoyl reductase enzyme, InhA, a validated target for TB drug discovery. These lead compounds inhibit the growth of both sensitive and drug resistant MTB strains with similar antibacterial potency (1-2 ug/mL), consistent with the hypothesis that compounds that do not require activation by the mycobacterial KatG enzyme will be active against isoniazid-resistant clinical strains. In response to RFA-AI-05-019, the goal of this proposal is to optimize the existing lead compounds to the point at which they can be used in preclinical trials for the treatment of patients infected with drug resistant TB. The proposed research includes the following specific aims.
Aim 1 : The existing lead compounds will be rationally modified to improve their in vitro and in vivo activity. Proposed structural modifications are designed to (i) decrease in the Ki for enzyme inhibition, (ii) improve critical in vivo parameters such as solubility and biological half-life and (iii) improve penetration into MTB cells.
Aim 2 : Focused compound libraries will be synthesized to (i) explore chemical space around the existing lead compounds and (ii) generate compounds with different chemical scaffolds in order to expand the chemical diversity of the InhA inhibitors.
Aim 3 : The in vitro and in vivo activity of compounds from Aims 1 and 2 will be determined. Primary screens will involve IC50 (InhA), MIC (sensitive and MDR TB strains) and cytotoxicity measurements. Secondary screens will provide toxicity (MTD) and bioavailability estimates, prior to assessing in vivo antibacterial activity. The mode of compound action in live bacteria and the mechanism of enzyme inhibition will be assessed. Tertiary screens will determine antibacterial activity in short (GKO) and long term animal models of TB infection. Detailed pharmacokinetic and pharmacodynamic studies will be performed on select compounds. Information from the screens in Aim 3 will be used to direct the synthesis of further compounds. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI070383-03
Application #
7492877
Study Section
Special Emphasis Panel (ZAI1-GSM-M (M1))
Program Officer
Lacourciere, Karen A
Project Start
2006-08-15
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$615,510
Indirect Cost
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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