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Antimicrobial Agents and Chemotherapy, April 2007, p. 1234-1239, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01040-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Activities of DL-{alpha}-Difluoromethylarginine and Polyamine Analogues against Cryptosporidium parvum Infection in a T-Cell Receptor Alpha-Deficient Mouse Model{triangledown}

Nigel Yarlett,1,2* W. Ray Waters,3 James A. Harp,3 Michael J. Wannemuehler,4 Mary Morada,1 Josephine Bellcastro,1 Steve J. Upton,5 Laurence J. Marton,6 and Benjamin J. Frydman7

Haskins Laboratories,1 Department of Chemistry and Physical Sciences, Pace University, New York, New York 10038,2 National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, Iowa 50010,3 Veterinary Medical Research Institute, Iowa State University, Ames, Iowa 50011,4 Kansas State University, Manhattan, Kansas 66506,5 Cellgate, Redwood City, California 94065,6 Omnisynthesis LLC, Madison, Wisconsin 537117

Received 19 August 2006/ Returned for modification 18 October 2006/ Accepted 8 January 2007

The in vivo effectiveness of a series of conformationally restricted polyamine analogues alone and selected members in combination with DL-{alpha}-difluoromethylarginine against Cryptosporidium parvum infection in a T-cell receptor alpha-deficient mouse model was tested. Polyamine analogues were selected from the extended bis(ethyl)-sym-homospermidine or bis(ethyl)-spermine 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 infection in a mouse model than the trans polyamine analogues when tested in a T-cell receptor alpha-deficient mouse model. When tested in combination with DL-{alpha}-difluoromethylarginine, the cis-restricted analogues were found to be more effective in preventing oocyst shedding. This study demonstrates the potential of polyamine analogues as anticryptosporidial agents and highlights the presence of multiple points in polyamine synthesis by this parasite that are susceptible to inhibition resulting in growth inhibition.

* Corresponding author. Mailing address: Haskins Laboratories, Pace University, 41 Park Row, New York, NY 10038. Phone: (212) 346-1853. Fax: (212) 346-1586. E-mail: nyarlett{at}pace.edu

{triangledown} Published ahead of print on 22 January 2007.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1234-1239, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01040-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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