Submitted to: Antimicrobial Agents and Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/8/2007
Publication Date: 1/22/2007
Citation: Yarlett, N., Waters, W.R., Harp, J.A., Wannemuehler, M.J., Morada, M., Bellcastro, J., Upton, S.J., Marton, L.J., Frydman, B.J. 2007. Activity of DL-alpha-Difluoromethylarginine and Polyamine Analogues against Cryptosporidium parvum Infection in a T-Cell Receptor Alpha-Deficient Mouse Model. Antimicrobial Agents and Chemotherapy. 51(4):1234-1239. Interpretive Summary: Cryptospordium parvum is an intestinal parasite that causes diarrheal disease in calves. This disease is costly to dairy and beef producers, and the disease can also spread to humans. There are no effective drug treatments available for this parasite. In this study, we demonstrate a new class of compounds effective in the prevention and treatment of Cryptosporidium parvum infection of mice. Further study of these compounds may lead to effective treatment and prevention strategies for controlling Cryptosporidium parvum infection of cattle.
Technical Abstract: The in vivo effectiveness of a series of conformationally restricted polyamine analogs alone and in combination with DL-alpha-difluoromethylarginine (DFMA) towards a T-cell receptor-alpha deficient mouse model infection of Cryptosporidium parvum was tested. Polyamine analogues were constructed from the extended bis(ethyl)-symhomospermidine (BE-4-4-4) or bis(ethyl)-spermine (BE-3-4-3) backbone having cis or trans double bonds at the center of the molecule. The cis-isomers were found to have significantly greater efficacy in both preventing and curing a mouse model infection than the trans polyamine analogues when tested in a T-cell receptor-alpha deficient mouse model. When tested in combination with DL-alpha-diflouromethylarginine the cis-restricted analogues were found to be more effective in preventing oocyst shedding. This study demonstrates the potential of polyamine analogues as antiparasitic agents and highlights the complexity of this pathway that requires the utilization of multiple agents to block polyamine synthesis and result in growth inhibition.