Many Gram-positive bacteria including Mycobacterium tuberculosis, Listeria monocytogenes and Staphylococcus aureus are pathogens with significant impact on human suffering, and potentially, bioterrorism worldwide. With increasing levels of drug resistance in virtually all pathogens there is significant interest n the development of new drugs. The World Health Organization (WHO) published a goal of having 21 new or repurposed anti-tuberculosis drugs in Phase 1 clinical trials by 2015. Reaching this goal will require a tremendous investment in effort and money; however, new drugs to combat these pathogens would help reduce human suffering and potentially counter the threat of bioterrorism. The pathogens mentioned above are obligate aerobic Gram-positives, utilizing menaquinone as the sole lipoquinone in their electron transport chain. This suggests that menaquinone synthesis may present a potential drug target in all. Although the work proposed here is applicable to most Gram-positive organisms, emphasis has been placed on M. tuberculosis. Thus, the overriding goal of this project is to identify new compounds that have the potential for entering the drug development pipeline and helping to meet the WHO goals. We have previously demonstrated that menaquinone synthesis is a viable druggable target and identified enzymes involved in menaquinone synthesis in mycobacteria that were previously unknown and, which may also provide potential new drug targets. In this project we will refine our lead compounds via medicinal chemistry guided by enzyme kinetics, evaluate mechanisms of action for these new compounds and study the physiological importance of novel enzymes identified to be involved in mycobacterial menaquinone synthesis. If funded, the project will generate new and improved anti-TB compounds based on our current lead compound, identify new pharmacophores that inhibit various aspects of oxidative phosphorylation, identify previously unknown drug targets and significantly advance our understanding of how mycobacteria are able to regulate oxygen consumption and ATP synthesis in the hypoxic conditions found in the granulomas of infected lungs.
The goal of this proposal is to develop novel inhibitors of menaquinone biosynthesis in Mycobacterium tuberculosis, which will potentially generate new lead compounds and eventually new drugs for the treatment of tuberculosis.
|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