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.
|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|
|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|
|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|
|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|
|DaffÃ©, Mamadou; Crick, Dean C; Jackson, Mary (2014) Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids. Microbiol Spectr 2:|
|DaffÃ©, Mamadou; Crick, Dean C; Jackson, Mary (2014) Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids. Microbiol Spectr 2:MGM2-0021-2013|
|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|
|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 35 publications