title: Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance.
abstract: Cycloguanil, the active metabolite of the antimalarial drug proguanil, is an inhibitor of dihydrofolate reductase as is another antimalarial, pyrimethamine. Its use has been limited by the rapid development of resistance by parasites around the world. We have determined the cycloguanil- and pyrimethamine-sensitivity status of 10 isolates of Plasmodium falciparum and have sequenced in all these isolates the dihydrofolate reductase (DHFR; 5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) portion of the DHFR-thymidylate synthase (TS; 5,10-methylenetetrahydrofolate: dUMP C-methyltransferase, EC 2.1.1.45) gene. Instead of the known serine-to-asparagine change at position 108 that is important in pyrimethamine resistance, a serine-to-threonine change at the same position is found in cycloguanil-resistant isolates along with an alanine-to-valine change at position 16. We conclude that pyrimethamine and cycloguanil resistance most commonly involve alternative mutations at the same site. However, we also have identified a parasite with a unique set of changes that results in resistance to both drugs.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Foote
authors.forename: D
authors.initials: D
authors.lastname: Galatis
authors.forename: A F
authors.initials: AF
authors.lastname: Cowman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004351:Drug Resistance / Q000235:genetics; D005796:Genes; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D002727:Proguanil; D011739:Pyrimethamine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D013940:Thymidylate Synthase / Q000235:genetics*; D014227:Triazines / Q000494:pharmacology*
chemical_list: D015345:Oligonucleotide Probes; D014227:Triazines; C026009:cycloguanil; D004247:DNA; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D002727:Proguanil; D011739:Pyrimethamine