Abstract

Dr. Sibley and coworkers have expressed both dihydrofolate reductase and dihydropteroate synthase from Plasmodium falciparum in the budding yeast, Saccharomyces cerevisiae and shown that one can study the parasite enzymes in this simple system. When completed their experiments will provide a detailed understanding of the mutations that modify function of the Pf-DHFR and Pf-DHPS enzymes or sensitivity of the enzymes to antifolate drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042321-04
Application #
6373759
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Gottlieb, Michael
Project Start
1998-07-15
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$237,185
Indirect Cost

  Institution

Name
University of Washington
Department
Genetics
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Bates, Sarah J; Winstanley, Peter A; Watkins, William M et al. (2004) Rare, highly pyrimethamine-resistant alleles of the Plasmodium falciparum dihydrofolate reductase gene from 5 African sites. J Infect Dis 190:1783-92
Nzila, A M; Mberu, E K; Nduati, E et al. (2002) Genetic diversity of Plasmodium falciparum parasites from Kenya is not affected by antifolate drug selection. Int J Parasitol 32:1469-76
Hastings, Michele D; Bates, Sarah J; Blackstone, Eric A et al. (2002) Highly pyrimethamine-resistant alleles of dihydrofolate reductase in isolates of Plasmodium falciparum from Tanzania. Trans R Soc Trop Med Hyg 96:674-6
Mberu, Edward K; Nzila, Alexis M; Nduati, Eunice et al. (2002) Plasmodium falciparum: in vitro activity of sulfadoxine and dapsone in field isolates from Kenya: point mutations in dihydropteroate synthase may not be the only determinants in sulfa resistance. Exp Parasitol 101:90-6
Ferlan, J T; Mookherjee, S; Okezie, I N et al. (2001) Mutagenesis of dihydrofolate reductase from Plasmodium falciparum: analysis in Saccharomyces cerevisiae of triple mutant alleles resistant to pyrimethamine or WR99210. Mol Biochem Parasitol 113:139-50
Hankins, E G; Warhurst, D C; Sibley, C H (2001) Novel alleles of the Plasmodium falciparum dhfr highly resistant to pyrimethamine and chlorcycloguanil, but not WR99210. Mol Biochem Parasitol 117:91-102
Lau, H; Ferlan, J T; Brophy, V H et al. (2001) Efficacies of lipophilic inhibitors of dihydrofolate reductase against parasitic protozoa. Antimicrob Agents Chemother 45:187-95
Nzila, A M; Mberu, E K; Sulo, J et al. (2000) Towards an understanding of the mechanism of pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: genotyping of dihydrofolate reductase and dihydropteroate synthase of Kenyan parasites. Antimicrob Agents Chemother 44:991-6
Nzila, A M; Nduati, E; Mberu, E K et al. (2000) Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate Pyrimethamine/Sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. J Infect Dis 181:2023-8
Brophy, V H; Vasquez, J; Nelson, R G et al. (2000) Identification of Cryptosporidium parvum dihydrofolate reductase inhibitors by complementation in Saccharomyces cerevisiae. Antimicrob Agents Chemother 44:1019-28

Showing the most recent 10 out of 11 publications