ABSTRACT
Resistance to the antimalarial drug sulfadoxine-pyrimethamine (SP) emerged in Plasmodium falciparum from Asia in the 1960s and subsequently spread to Africa. It is not known whether alleles that confer SP resistance also arose independently in Africa. We defined the coding region and microsatellite haplotypes of dhfr alleles in P. falciparum collected in Kilifi, Kenya, during 1987--2006, which spans the period when SP was first introduced. Isolates that carried a double-mutant or triple-mutant dhfr allele were detected at a low frequency, even during 1987--1988. Each of 2 double mutants carried a unique haplotype, and both were related to wild-type haplotypes from the same population. The number of isolates that carried a triple-mutant dhfr allele increased rapidly after introduction of SP and shared the haplotype of the triple mutant derived form Asia. We observed no triple-mutant alleles with haplotypes related to those of the Africa-derived wild-type and double-mutant alleles.
Subject(s)
Antimalarials/pharmacology , Drug Resistance/genetics , Haplotypes , Plasmodium falciparum/drug effects , Plasmodium falciparum/genetics , Pyrimethamine/pharmacology , Animals , Gene Frequency , Humans , Kenya/epidemiology , Malaria, Falciparum/epidemiology , Malaria, Falciparum/parasitology , Microsatellite Repeats , Time FactorsSubject(s)
4-Aminobenzoic Acid/antagonists & inhibitors , Anti-Infective Agents/pharmacology , Dihydropteroate Synthase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Sulfonamides/pharmacology , 4-Aminobenzoic Acid/pharmacology , Animals , Drug Resistance , Escherichia coli/drug effects , Escherichia coli/enzymology , Escherichia coli/growth & development , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Plasmodium falciparum/growth & development , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae/growth & development , Transaminases/antagonists & inhibitorsABSTRACT
Plasmodium falciparum parasites resistant to the combination sulfadoxine-pyrimethamine are spreading in Africa, particularly in East Africa. This is a matter of concern because there are no other affordable drugs available. This article provides the evidence indicating that sulfadoxine-pyrimethamine resistance can be reversed in vitro and discusses how this information might be exploited to extend the therapeutic lifetime of sulfadoxine-pyrimethamine in vivo.
Subject(s)
Antimalarials/pharmacology , Folic Acid Antagonists/pharmacology , Plasmodium falciparum/drug effects , Probenecid/pharmacology , Pyrimethamine/pharmacology , Sulfadoxine/pharmacology , Animals , Antimalarials/therapeutic use , Drug Combinations , Drug Resistance/drug effects , Drug Synergism , Drug Therapy, Combination , Folic Acid/drug effects , Folic Acid/metabolism , Folic Acid Antagonists/therapeutic use , Malaria, Falciparum/drug therapy , Plasmodium falciparum/metabolism , Probenecid/therapeutic use , Pyrimethamine/therapeutic use , Sulfadoxine/therapeutic useABSTRACT
We have determined the relationship between point mutations in the gene that encodes the sulfa target, dihydropteroate synthase (DHPS) and the chemosensitivity profile to sulfadoxine and dapsone in 67 isolates from Kilifi, Kenya. We assessed the presence of mutations at codons 436, 437, 540, 581, and 613 of dhps. The results showed that the dhps genotype had a strong influence on the sensitivity to sulfadoxine and dapsone, but that the correlation was far from perfect. Eleven isolates carried a wild-type dhps allele, but were resistant to sulfadoxine (IC(50) values >10 microg/ml), and 4/28 isolates were classed as sensitive to sulfadoxine (IC(50) values <10 microg/ml), but carried a triple mutant (436/437/613) allele of dhps. These data show that in low folate medium in vitro, the dhps genotype alone did not account completely for sulfadoxine or dapsone resistance; other factors such as the utilisation of exogenous folate must also be considered.
