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Eukaryotic Cell, April 2009, p. 483-486, Vol. 8, No. 4
1535-9778/09/$08.00+0     doi:10.1128/EC.00298-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Towards New Antifolates Targeting Eukaryotic Opportunistic Infections{triangledown}

Jieying Liu, David B. Bolstad, Erin S. D. Bolstad, Dennis L. Wright, and Amy C. Anderson*

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269

Received 9 September 2008/ Accepted 8 November 2008

Trimethoprim, an antifolate commonly prescribed in combination with sulfamethoxazole, potently inhibits several prokaryotic species of dihydrofolate reductase (DHFR). However, several eukaryotic pathogenic organisms are resistant to trimethoprim, preventing its effective use as a therapeutic for those infections. We have been building a program to reengineer trimethoprim to more potently and selectively inhibit eukaryotic species of DHFR as a viable strategy for new drug discovery targeting several opportunistic pathogens. We have developed a series of compounds that exhibit potent and selective inhibition of DHFR from the parasitic protozoa Cryptosporidium and Toxoplasma as well as the fungus Candida glabrata. A comparison of the structures of DHFR from the fungal species Candida glabrata and Pneumocystis suggests that the compounds may also potently inhibit Pneumocystis DHFR.

* Corresponding author. Mailing address: Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd., Storrs, CT 06269. Phone: (860) 486-6145. Fax: (860) 486-6857. E-mail: amy.anderson{at}uconn.edu

{triangledown} Published ahead of print on 23 January 2009.

Eukaryotic Cell, April 2009, p. 483-486, Vol. 8, No. 4
1535-9778/09/$08.00+0     doi:10.1128/EC.00298-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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