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 proposal are to: 1) Design, synthesize and test a new class of anti-tuberculosis agents derived from an oxidosqualene cyclase inhibitor. 2) test MenA, GrcC1, GrcC2, Rv0558 and Rv3853, genes hypothesized to participate in menaquinone synthesis in M. tuberculosis, for essentiality. 3) Define the mechanism of MenA catalysis, characterize the enzymatic properties of GrcC1, GrcC2, Rv0558 and Rv3853 and develop high-throughput screening compatible assays for those enzymes shown to be essential. Relevance: The results 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
High Priority, Short Term Project Award (R56)
Project #
2R56AI049151-05
Application #
7488671
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Goldman, Robert C
Project Start
2001-02-01
Project End
2008-03-14
Budget Start
2007-09-30
Budget End
2008-03-14
Support Year
5
Fiscal Year
2007
Total Cost
$320,260
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
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:
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
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: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
Mahapatra, Sebabrata; Piechota, Charles; Gil, Filipa et al. (2013) Mycobacteriophage Ms6 LysA: a peptidoglycan amidase and a useful analytical tool. Appl Environ Microbiol 79:768-73
Ishizaki, Yoshimasa; Hayashi, Chigusa; Inoue, Kunio et al. (2013) Inhibition of the first step in synthesis of the mycobacterial cell wall core, catalyzed by the GlcNAc-1-phosphate transferase WecA, by the novel caprazamycin derivative CPZEN-45. J Biol Chem 288:30309-19
Gee, Christine L; Papavinasasundaram, Kadamba G; Blair, Sloane R et al. (2012) A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria. Sci Signal 5:ra7

Showing the most recent 10 out of 18 publications