Characteristics of Plasmodium falciparum dhfr haplotypes that confer pyrimethamine resistance, Kilifi, Kenya, 1987--2006.

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.

[1]  Conner I. Sandefur,et al.  Pyrimethamine-resistant dihydrofolate reductase enzymes of Plasmodium falciparum are not enzymatically compromised in vitro. , 2007, Molecular and biochemical parasitology.

[2]  B. Sharp,et al.  Antifolate antimalarial resistance in southeast Africa: a population-based analysis , 2003, The Lancet.

[3]  D. Kariuki,et al.  Response of falciparum malaria to chloroquine and three second line antimalarial drugs in a Kenyan coastal school age population. , 1993, East African medical journal.

[4]  A. Saul,et al.  Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum , 2001, Parasitology.

[5]  O. Doumbo,et al.  Rapid selection of Plasmodium falciparum dihydrofolate reductase mutants by pyrimethamine prophylaxis. , 2000, The Journal of infectious diseases.

[6]  H. Bandelt,et al.  Median-joining networks for inferring intraspecific phylogenies. , 1999, Molecular biology and evolution.

[7]  M. Duraisingh,et al.  Plasmodium falciparum: detection of polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes by PCR and restriction digestion. , 1998, Experimental parasitology.

[8]  C. Plowe,et al.  Mechanisms of Resistance of Malaria Parasites to Antifolates , 2005, Pharmacological Reviews.

[9]  R. Snow,et al.  Chlorproguanil-dapsone: effective treatment for uncomplicated falciparum malaria , 1997, Antimicrobial agents and chemotherapy.

[10]  S. Meshnick,et al.  Epidemiology of drug-resistant malaria. , 2002, The Lancet. Infectious diseases.

[11]  J. T. Williams,et al.  Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. , 2000, Molecular biology and evolution.

[12]  O. Gaye,et al.  Defining the origin of Plasmodium falciparum resistant dhfr isolates in Senegal. , 2006, Acta tropica.

[13]  X. Su,et al.  Complex mutations in a high proportion of microsatellite loci from the protozoan parasite Plasmodium falciparum , 2000, Molecular ecology.

[14]  O. Doumbo,et al.  A shared Asian origin of the triple-mutant dhfr allele in Plasmodium falciparum from sites across Africa. , 2007, The Journal of infectious diseases.

[15]  J. Barnwell,et al.  Antifolate resistance in Plasmodium falciparum: multiple origins and identification of novel dhfr alleles. , 2006, The Journal of infectious diseases.

[16]  C. Sibley,et al.  Plasmodium falciparum: a novel method for analyzing haplotypes in mixed infections. , 2007, Experimental parasitology.

[17]  B. Sharp,et al.  Intercontinental Spread of Pyrimethamine-Resistant Malaria , 2004, Science.

[18]  K. Kain,et al.  Real-Time PCR Assay for Rapid Detection and Analysis of PfCRT Haplotypes of Chloroquine-Resistant Plasmodium falciparum Isolates from India , 2007, Journal of Clinical Microbiology.

[19]  R. Snow,et al.  Relationships between Plasmodium falciparum transmission by vector populations and the incidence of severe disease at nine sites on the Kenyan coast. , 1995, The American journal of tropical medicine and hygiene.

[20]  J. E. Hyde,et al.  Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? , 2001, Trends in parasitology.

[21]  W. Watkins,et al.  Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life. , 1993, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[22]  A. Craig,et al.  Limited spatial clustering of individual Plasmodium falciparum alleles in field isolates from coastal Kenya. , 1997, The American journal of tropical medicine and hygiene.

[23]  S. Masaba,et al.  Sensitivity of Plasmodium falciparum isolates to chloroquine in Kisumu and Malindi, Kenya. , 1982, The American journal of tropical medicine and hygiene.

[24]  C. Rogier,et al.  Rapid Dissemination of Plasmodium falciparum Drug Resistance Despite Strictly Controlled Antimalarial Use , 2007, PloS one.

[25]  C. Plowe,et al.  Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain , 1998, Antimicrobial Agents and Chemotherapy.

[26]  P. Olliaro,et al.  Averting a malaria disaster , 1999, The Lancet.

[27]  O. Doumbo,et al.  P. falciparum dihydrofolate reductase and dihydropteroate synthase mutations: epidemiology and role in clinical resistance to antifolates. , 1998, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[28]  A. Nzila,et al.  The changing in vitro susceptibility pattern to pyrimethamine/sulfadoxine in Plasmodium falciparum field isolates from Kilifi, Kenya. , 2000, The American journal of tropical medicine and hygiene.

[29]  J. Kublin,et al.  Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. , 2002, The Journal of infectious diseases.

[30]  P. Newton,et al.  A selective sweep driven by pyrimethamine treatment in southeast asian malaria parasites. , 2003, Molecular biology and evolution.