Abstract
To assess the relationship between mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) and clinical pyrimethamine-sulfadoxine resistance, polymerase chain reaction surveys and analyses for new mutations were conducted in four countries with increasing levels of pyrimethamine-sulfadoxine resistance: Mali, Kenya, Malawi, and Bolivia. Prevalence of mutations at DHFR codon 108 and a new mutation at DHPS 540 correlated with increased pyrimethamine-sulfadoxine resistance (P < .05). Mutations at DHFR 51, DHFR 59, and DHPS 437 correlated with resistance without achieving statistical significance. Mutations at DHFR 164 and DHPS 581 were common in Bolivia, where pyrimethamine-sulfadoxine resistance is widespread, but absent in African sites. Two new DHFR mutations, a point mutation at codon 50 and an insert at codon 30, were found only in Bolivia. DHFR and DHPS mutations occur in a progressive, stepwise fashion. Identification of specific sets of mutations causing in vivo drug failure may lead to the development of molecular surveillance methods for pyrimethamine-sulfadoxine resistance.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Africa / epidemiology
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Amino Acid Sequence
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Animals
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Antimalarials / pharmacology
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Antimalarials / therapeutic use*
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Base Sequence
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Bolivia / epidemiology
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Cloning, Molecular
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DNA, Protozoan / analysis
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DNA, Protozoan / genetics
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Dihydropteroate Synthase / genetics*
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Dihydropteroate Synthase / metabolism
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Drug Combinations
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Drug Resistance
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Humans
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Malaria, Falciparum / drug therapy
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Malaria, Falciparum / epidemiology
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Malaria, Falciparum / genetics
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Malaria, Falciparum / parasitology*
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Molecular Epidemiology
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Molecular Sequence Data
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Molecular Structure
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Mutagenesis, Insertional
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology
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Plasmodium falciparum / genetics*
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Point Mutation
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Polymerase Chain Reaction
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Prevalence
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Pyrimethamine / pharmacology
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Pyrimethamine / therapeutic use*
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Sulfadoxine / pharmacology
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Sulfadoxine / therapeutic use*
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Tetrahydrofolate Dehydrogenase / chemistry
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Tetrahydrofolate Dehydrogenase / genetics*
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Tetrahydrofolate Dehydrogenase / metabolism
Substances
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Antimalarials
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DNA, Protozoan
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Drug Combinations
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fanasil, pyrimethamine drug combination
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Sulfadoxine
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Tetrahydrofolate Dehydrogenase
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Dihydropteroate Synthase
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Pyrimethamine