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The genetics of resistance to antifolate and sulfa drugs in malaria parasites

Drug resistance is one of the major obstacles facing malaria control. Resistance to the combination sulfadoxine/pyrimethamine (S/P) (Fansidar) is now widespread, although the mechanism by which this arises is still not fully understood. Therefore, the molecular basis of S/P resistance was studied in the rodent malaria parasite, <i>Plasmodium chadaubi</i>. S/P resistant mutants were selected from a clone already resistant to the pyrimethamine, AS (PYR), caused by the presence of an asparagine at position 106 in its dihydrofolate reductase (DHFR). Two S/P resistant clones, AS (50S/P) and AS (75S/P), were selected and chosen for further analysis. AS (PYR) parasites were eliminated by S/P treatment, whereas AS (50S/P) and AS (75S/P) recrudesced following S/P pressure. However, each mutant possessed a different drug resistant phenotype. The AS (75S/P) clone always recrudesced before the AS (50S/P) clone following treatment with S/P, while AS (50S/P) always appeared before AS (75S/P) when treated with either sulfadoxine or pyrimethamine alone. Mutations in the genes encoding the targets of sulfadoxine and pyrimethamine, dihydropteroate synthase (DHPS) and DHFR, have been implicated in the mechanism of S/P resistance in <i>P. falciparum</i>. The <i>P. chabaudi</i> <i>dhps</i> gene was cloned by homology and sequenced. The sequence analysis of the both <i>dhfr</i> and <i>dhps</i> genes of AS (75S/P) and AS(50S/P) did not reveal any polymorphisms when compared to the sequences of the AS (PYR) genes. The mechanism of resistance of S/P in these drug-selected lines is not therefore conferred by additional mutations in these genes. To determine the genetic basis of the S/P resistance, AS (50S/P) was crossed with a drug sensitive clone, AJ. Sixteen independent recombinant progeny clones were phenotyped for their susceptibility to S/P and pyrimethamine and genotyped for the influence of 30 chromosome-specific markers. Linkage analysis shows that mutant <i>dhfr</i> is a major determinant of S/P resistance in <i>P. chabaudi</i>. Quantitative trait analysis suggested that other loci, which may be involved in S/P resistance, are present on chromosomes 4, 5, and 9.
Date January 2000
CreatorsHayton, Karen
PublisherUniversity of Edinburgh
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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