Cryptosporidium parvum is a protozoan parasite that causes severe disease in small children, pregnant women, the elderly, and those with a weakened immune system and contributes significantly to morbidity and mortality among AIDS patients. C. parvum is resistant to many water disinfection procedures and several large outbreaks in the US have been linked to drinking and recreational water contamination. There is a growing and credible concern that this organism could be deliberately introduced into the water supply in an act of bioterrorism. The tools to react to such an incident are woefully inadequate; no vaccine and no effective drug treatment are available for Cryptosporidium. New drugs are clearly needed to face this threat. C. parvum, like all parasitic protozoa, is entirely dependent on purine salvage from the host, making this pathway an extremely attractive drug target. We will delineate the purine uptake and salvage pathways of C. parvum. Our Preliminary Results suggest that inosine-5'-monophosphate-dehydrogenase (IMPDH) is a key enzyme in these pathways. IMPDH is a validated and clinically used drug target. Large and growing libraries of potential inhibitors are already available. This application proposes to study the biochemistry of IMPDH from C. parvum and to screen for potential lead inhibitors from existing compound libraries. Importantly, the peculiar 'extracytoplasmatic' position of the parasite within the infected cell has been associated with its resistance to many drugs. We will use C. parvum as well as suitable transgenic models to study the mechanisms of uptake and activation of nucleoside inhibitors. This work will provide urgently needed molecular reagents to understand the biology of nutrient uptake and drug resistance in this unique parasite. ? ? ?
| Sun, Xin E; Sharling, Lisa; Muthalagi, Mani et al. (2010) Prodrug activation by Cryptosporidium thymidine kinase. J Biol Chem 285:15916-22 |
| Umejiego, Nwakaso N; Gollapalli, Deviprasad; Sharling, Lisa et al. (2008) Targeting a prokaryotic protein in a eukaryotic pathogen: identification of lead compounds against cryptosporidiosis. Chem Biol 15:70-7 |
| Riera, Thomas V; Wang, Wen; Josephine, Helen R et al. (2008) A kinetic alignment of orthologous inosine-5'-monophosphate dehydrogenases. Biochemistry 47:8689-96 |
| Galazka, Jon; Striepen, Boris; Ullman, Buddy (2006) Adenosine kinase from Cryptosporidium parvum. Mol Biochem Parasitol 149:223-30 |
| Haslam, J L; Egodage, K L; Chen, Y et al. (1999) Stability of rifabutin in two extemporaneously compounded oral liquids. Am J Health Syst Pharm 56:333-6 |
