This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jiang, L.
Right arrow Articles by Rathod, P. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jiang, L.
Right arrow Articles by Rathod, P. K.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2000, p. 1047-1050, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Potent and Selective Activity of a Combination of Thymidine and 1843U89, a Folate-Based Thymidylate Synthase Inhibitor, against Plasmodium falciparum

Lei Jiang, Pei-Chieh Lee, John White, and Pradipsinh K. Rathod*

Department of Biology, The Catholic University of America, Washington, DC 20064

Received 2 September 1999/Returned for modification 19 October 1999/Accepted 30 December 1999

Unlike mammalian cells, malarial parasites are completely dependent on the de novo pyrimidine pathway and lack the enzymes to salvage preformed pyrimidines. In the present study, first, it is shown that 1843U89, even without polyglutamylation, is a potent folate-based inhibitor of purified malarial parasite thymidylate synthase. The binding was noncompetitive with respect to methylenetetrahydrofolate, and 1843U89 had a Ki of 1 nM. The compound also had potent antimalarial activity in vitro. Plasmodium falciparum cells in culture were inhibited by 1843U89, with a 50% inhibitory concentration of about 70 nM. The compound was effective against drug-sensitive as well as drug-resistant clones of P. falciparum. As predicted by the biochemistry of the parasite, the potent inhibition of parasite proliferation by 1843U89 could not be reversed with 10 µM thymidine. In contrast, in the presence of 10 µM thymidine, mammalian cells were unaffected by 1843U89 even at concentrations as high as 0.1 mM, thus offering a selectivity window of more than 1,000-fold. On this basis, folate-based thymidylate synthase inhibitors may represent a powerful additional tool that can be used to combat drug-resistant malaria.

* Corresponding author. Mailing address: Department of Biology, The Catholic University of America, 620 Michigan Ave. NE, Washington, DC 20064. Phone: (202) 319-5278. Fax: (202) 319-5721. E-mail: rathod{at}cua.edu.

Antimicrobial Agents and Chemotherapy, April 2000, p. 1047-1050, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Aboge, G. O., Jia, H., Terkawi, M. A., Goo, Y.-K., Nishikawa, Y., Sunaga, F., Namikawa, K., Tsuji, N., Igarashi, I., Suzuki, H., Fujisaki, K., Xuan, X. (2008). Cloning, Expression, and Characterization of Babesia gibsoni Dihydrofolate Reductase-Thymidylate Synthase: Inhibitory Effect of Antifolates on Its Catalytic Activity and Parasite Proliferation. Antimicrob. Agents Chemother. 52: 4072-4080 [Abstract] [Full Text]  
  • Nzila, A. (2006). The past, present and future of antifolates in the treatment of Plasmodium falciparum infection. J Antimicrob Chemother 57: 1043-1054 [Abstract] [Full Text]  
  • Eastman, R. T., White, J., Hucke, O., Bauer, K., Yokoyama, K., Nallan, L., Chakrabarti, D., Verlinde, C. L. M. J., Gelb, M. H., Rathod, P. K., Van Voorhis, W. C. (2005). Resistance to a Protein Farnesyltransferase Inhibitor in Plasmodium falciparum. J. Biol. Chem. 280: 13554-13559 [Abstract] [Full Text]  
  • Vestereng, V. H., Kovacs, J. A. (2004). Inability of Pneumocystis organisms to incorporate bromodeoxyuridine suggests the absence of a salvage pathway for thymidine. Microbiology 150: 1179-1182 [Abstract] [Full Text]  
  • Yeh, I., Hanekamp, T., Tsoka, S., Karp, P. D., Altman, R. B. (2004). Computational Analysis of Plasmodium falciparum Metabolism: Organizing Genomic Information to Facilitate Drug Discovery. Genome Res 14: 917-924 [Abstract] [Full Text]  
  • Baldwin, J., Farajallah, A. M., Malmquist, N. A., Rathod, P. K., Phillips, M. A. (2002). Malarial Dihydroorotate Dehydrogenase. SUBSTRATE AND INHIBITOR SPECIFICITY. J. Biol. Chem. 277: 41827-41834 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»