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dc.contributor.authorWorachart Sirawarapornen_US
dc.contributor.authorTanajit Sathitkulen_US
dc.contributor.authorRachada Sirawarapornen_US
dc.contributor.authorYongyuth Yuthavongen_US
dc.contributor.authorDaniel V. Santien_US
dc.contributor.otherMahidol Universityen_US
dc.contributor.otherUniversity of California, San Franciscoen_US
dc.contributor.otherThailand National Science and Technology Development Agencyen_US
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America. Vol.94, No.4 (1997), 1124-1129en_US
dc.description.abstractSingle and multiple mutations at residues 16, 51, 59, 108, and 164 of Plasmodium falciparum dihydrofolate reductase (pfDHFR) have been linked to antifolate resistance in malaria. We prepared and characterized all seven of the pfDHFR mutants found in nature, as well as six mutants not observed in nature. Mutations involving residues 51, 59, 108, or 164 conferred cross resistance to both the antifolates pyrimethamine and cycloguanil, whereas mutation of residue 16 specifically conferred resistance to cycloguanil. The antifolate resistance of enzyme mutants found in nature correlated with in vivo antifolate resistance; however, mutants not found in nature were either poorly resistant or had insufficient catalytic activity to support DNA synthesis. Thus, specific combinations of multiple mutations at target residues were selected in nature to optimize resistance. Further, the resistance of multiple mutants was more than the sum of the component single mutations, indicating that residues were selected for their synergistic as well as intrinsic effects on resistance. Pathways inferred for the evolution of pyrimethamine-resistant mutants suggested that all multiple mutants emerged from stepwise selection of the single mutant, S108N. Thus, we propose that drugs targeted to both the wild-type pfDHFR and S108N mutant would have a low propensity for developing resistance, and hence could provide effective antimalarial agents.en_US
dc.rightsMahidol Universityen_US
dc.subjectBiochemistry, Genetics and Molecular Biologyen_US
dc.titleAntifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductaseen_US
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