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Antimicrobial Agents and Chemotherapy, November 2006, p. 3631-3637, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00448-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Evaluation of the Activities of Pyrimethamine Analogs against Plasmodium vivax and Plasmodium falciparum Dihydrofolate Reductase-Thymidylate Synthase Using In Vitro Enzyme Inhibition and Bacterial Complementation Assays{triangledown}

Sasinee Bunyarataphan, Ubolsree Leartsakulpanich,* Supannee Taweechai, Bongkoch Tarnchompoo, Sumalee Kamchonwongpaisan, and Yongyuth Yuthavong

National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, 113 Paholyothin Road, Pathumthani 12120, Thailand

Received 10 April 2006/ Returned for modification 2 June 2006/ Accepted 28 August 2006

Pyrimethamine analogs were examined as potential agents against vivax malaria using a bacterial surrogate system carrying Plasmodium vivax dihydrofolate reductase-thymidylate synthase (PvDHFR-TS), in which the PvDHFR complemented chemically knocked out host dihydrofolate reductase. The system was initially tested with P. falciparum dihydrofolate reductase-thymidylate synthase and was found to have good correlation with the parasite-based system. The 50% inhibitory concentrations derived from PvDHFR-TS-dependent bacteria were correlated with their corresponding inhibition constants (Ki) from an enzyme inhibition assay, pointing to the likelihood that the potent enzyme inhibitors will also have potent antimalarial activities. Active compounds against both wild-type and S58R S117N (SP21) double-mutant P. vivax include analogs with structures which can avert a steric clash with the asparagine (S117N) side chain of the mutant, similar to those found for homologous Plasmodium falciparum mutants, raising the possibility that the same compounds can be developed against both types of antifolate-resistant malaria. This rapid and convenient drug screening system should be useful for development of new antifolates against P. vivax, for which a continuous culture system is not yet available.

* Corresponding author. Mailing address: National Center for Genetic Engineering and Biotechnology, 113 Paholyothin Rd., Klong 1, Klong Luang, Pathumthani 12120, Thailand. Phone: 66-2-564-6700, ext. 3487. Fax: 662-564-6705. E-mail: ubolsree{at}biotec.or.th.

{triangledown} Published ahead of print on 5 September 2006.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3631-3637, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00448-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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