Potent inhibitors of menaquinone synthesis (specifically MenA) in M. tuberculosis have been identified, which are also effective inhibitors of mycobacterial growth. Since utilization of menaquinone is a characteristic of Gram-positive organisms, these compounds are also active against organisms such as methicillin resistant Stapylococcus aureus and Staphylococcus epidermidis, and are expected to be effective against Bacillus anthracis and Listeria monocytogenes as well. The compounds identified as MenA inhibitors here, were first developed as cholesterol synthesis inhibitors and, as such, are known to be bioavailable in mammals and to have low intrinsic toxicity. These compounds will be """"""""retro-designed"""""""" via cycle of synthetic medicinal chemistry followed by evaluation of compounds as menaquinone, and bacterial growth inhibitors. The compounds will also be counter-selected to reduce their effectiveness as cholesterol synthesis inhibitors. In addition, the mechanism of catalysis of MenA and alternative drug targets involved in menaquinone synthesis will be identified.
The Specific Aims of this application are to: 1) test MenA, GrcC1, GrcC2 and Rv0558 genes hypothesized to participate in menaquinone synthesis in M. tuberculosis, for essentiality. 2) Design, synthesize and test a new class of anti-tuberculosis agents derived from an oxidosqualene cyclase inhibitor. 3) Define the mechanism of MenA catalysis, characterize the enzymatic properties of GrcC1 and Rv0558 and develop high-throughput screening compatible assays for those enzymes shown to be essential. The results of this research program are expected to be of significance in terms of discovering new lead compounds that can be developed into new drugs to combat Gram-positive NIAID category A, B and C priority pathogens, as well as, emerging diseases caused by Gram-positive bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049151-06
Application #
7585169
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Lacourciere, Karen A
Project Start
2001-02-01
Project End
2012-02-29
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
6
Fiscal Year
2009
Total Cost
$336,931
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
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