Mutations in dhfr in Plasmodium falciparum infections selected by chlorproguanil-dapsone treatment.

Abstract

Treatment with the novel antifolate drug combination chlorproguanil-dapsone effectively cleared asymptomatic Plasmodium falciparum infections in 246 (93.5%) of 263 children in the Usambara Mountains of Tanzania during the course of a 2-week follow-up. Samples from 71 recurrent infections, collected over a 9-week follow-up, showed selection for parasites with the triple mutant Ile(51)-Arg(59)-Asn(108) in dihydrofolate reductase. There was no selection for mutations in dihydropteroate synthetase, the target enzyme of dapsone. Search for complete identity in the highly polymorphic genes coding for merozoite surface proteins 1 and 2 in parasite samples collected before and after treatment indicated that the majority of recurrent parasitemias were new infections. These observations on selection in Tanzania and the lack of selection reported from a less endemic area suggest that the active metabolite of chlorproguanil, which has a short half-life in the blood, may persist in the liver, where it exerts selective pressure on growing preerythrocytic stages.

• Authors: J Curtis, C A Maxwell, F H M Msuya, S Mkongewa, A Alloueche, D C Warhurst
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 186 Issue 12 Pg. 1861-4 (Dec 15 2002) ISSN: 0022-1899 [Print] United States
• PMID: 12447777 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Merozoite Surface Protein 1
• Dapsone
• Tetrahydrofolate Dehydrogenase
• Dihydropteroate Synthase
• Proguanil

Topics

• Animals
• Antimalarials (therapeutic use)
• Child
• Child, Preschool
• Dapsone (therapeutic use)
• Dihydropteroate Synthase (genetics)
• Drug Therapy, Combination
• Follow-Up Studies
• Genes, Protozoan
• Humans
• Infant
• Malaria, Falciparum (drug therapy, enzymology)
• Merozoite Surface Protein 1 (analysis)
• Mutation
• Parasitemia
• Plasmodium falciparum (enzymology, genetics)
• Proguanil (therapeutic use)
• Tanzania
• Tetrahydrofolate Dehydrogenase (genetics)