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 #
5R01AI049151-07
Application #
7770889
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
2010-03-01
Budget End
2011-02-28
Support Year
7
Fiscal Year
2010
Total Cost
$333,745
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
Kokoczka, Rachel; Schuessler, Dorothée L; Early, Julie V et al. (2017) Mycobacterium tuberculosis Rv0560c is not essential for growth in vitro or in macrophages. Tuberculosis (Edinb) 102:3-7
Tran, Anh T; Watson, Emma E; Pujari, Venugopal et al. (2017) Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis. Nat Commun 8:14414
Cook, Gregory M; Hards, Kiel; Dunn, Elyse et al. (2017) Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions. Microbiol Spectr 5:
Li, Kai; Wang, Yang; Yang, Gyongseon et al. (2015) Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109: Bacterial and Protozoal Cell Growth Inhibitors. ACS Infect Dis 1:215-221
Upadhyay, Ashutosh; Fontes, Fabio L; Gonzalez-Juarrero, Mercedes et al. (2015) Partial Saturation of Menaquinone in Mycobacterium tuberculosis: Function and Essentiality of a Novel Reductase, MenJ. ACS Cent Sci 1:292-302
Kuznetsov, Ilya; Filevich, Jorge; Dong, Feng et al. (2015) Three-dimensional nanoscale molecular imaging by extreme ultraviolet laser ablation mass spectrometry. Nat Commun 6:6944
Daffé, Mamadou; Crick, Dean C; Jackson, Mary (2014) Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids. Microbiol Spectr 2:MGM2-0021-2013
Li, Kai; Schurig-Briccio, Lici A; Feng, Xinxin et al. (2014) Multitarget drug discovery for tuberculosis and other infectious diseases. J Med Chem 57:3126-39
Li, Wei; Upadhyay, Ashutosh; Fontes, Fabio L et al. (2014) Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis. Antimicrob Agents Chemother 58:6413-23
Daffé, Mamadou; Crick, Dean C; Jackson, Mary (2014) Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids. Microbiol Spectr 2:

Showing the most recent 10 out of 42 publications