title: Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain.
abstract: Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P < 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 +/- 6.94 and 0.24 +/- 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).
authors.affiliation: Wellcome Trust Research Laboratories, Kenya Medical Research Institute, Nairobi. wellcome@users.africaonline.co.ke
authors.forename: A
authors.initials: A
authors.lastname: Nzila-Mounda
authors.forename: E K
authors.initials: EK
authors.lastname: Mberu
authors.forename: C H
authors.initials: CH
authors.lastname: Sibley
authors.forename: C V
authors.initials: CV
authors.lastname: Plowe
authors.forename: P A
authors.initials: PA
authors.lastname: Winstanley
authors.forename: W M
authors.initials: WM
authors.lastname: Watkins
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D006801:Humans; D007630:Kenya; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D017354:Point Mutation; D002727:Proguanil / Q000031:analogs & derivatives* / Q000494:pharmacology; D015800:Protozoan Proteins / Q000187:drug effects / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000235:genetics*; D014227:Triazines
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D014227:Triazines; C026009:cycloguanil; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D011739:Pyrimethamine