Sulfadoxine-pyrimethamine resistance in the rodent malaria parasite Plasmodium chabaudi.
We have studied resistance to sulfadoxine-pyrimethamine (S/P) in the rodent malaria parasite Plasmodium chabaudi. A stable S/P-resistant mutant, AS(50S/P), was selected by drug treatment of a clone, AS(PYR), already resistant to pyrimethamine. The sequences of the P. chabaudi dhfr and dhps genes were obtained and found to be identical in AS(50S/P) and AS(PYR), showing that resistance to S/P in AS(50S/P) was not due to additional mutations in either gene. AS(50S/P) was crossed with a drug-sensitive clone, AJ, and 16 independent recombinant progeny were obtained. These clones were phenotyped for their susceptibility to S/P and to sulfadoxine and pyrimethamine separately. Pyrimethamine resistance was invariably associated with S/P resistance, but no correlation was found between resistance to S/P and resistance to sulfadoxine. Quantitative trait locus analysis of the progeny with 31 chromosome-specific markers showed that mutant P. chabaudi dhfr, or one or more genes closely linked to it, was a major determinant of S/P resistance. In addition, the inheritance of genes on chromosomes 5 and 13 from the sensitive parent appeared to contribute to the level of resistance observed. These results demonstrate that the S/P resistance of the AS(50S/P) mutant of P. chabaudi does not involve mutation in dhps and is not due simply to a combination of two genes determining resistance to pyrimethamine and sulfadoxine separately.
Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh EH9 3JT, Scotland, UK.
Karen
K
Hayton
Lisa C
LC
Ranford-Cartwright
David
D
Walliker
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002875:Chromosomes / Q000235:genetics; D003433:Crosses, Genetic; D004094:Dihydropteroate Synthase / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D004351:Drug Resistance; D017125:Genes, Protozoan / Q000235:genetics; D005819:Genetic Markers; D008969:Molecular Sequence Data; D009115:Muridae; D009154:Mutation; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D013413:Sulfadoxine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism
D000962:Antimalarials; D004338:Drug Combinations; D005819:Genetic Markers; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine