Dihydrofolate reductase and dihydropteroate synthase genotypes associated with in vitro resistance of Plasmodium falciparum to pyrimethamine, trimethoprim, sulfadoxine, and sulfamethoxazole.
A total of 70 Plasmodium falciparum isolates were tested in vitro against pyrimethamine (PYR), trimethoprim (TRM), sulfadoxine (SDX), and sulfamethoxazole (SMX), and their dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genotypes were determined. dhfr genotypes correlated with PYR and TRM drug responses (r = 0.93 and 0.85). Isolates with wild-type alleles showed mean half inhibitory concentrations (IC50 +/- SD) of 0.10 +/- 0.10 and 0.15 +/- 0.06 microg/100 microl for PYR and TRM. Parasites with mutations at codons 108 and 51 alone or combined with codon 59 have IC50 of 11.46 +/- 0.86 (PYR) and 2.90 +/- 0.59 microg/100 microl (TRM). For both drugs, the differences in the mean IC50 between wild and mutant parasites were statistically significant (P < 0.001). Isolates with mixed wild and mutant alleles showed an intermediate level of susceptibility. Our data show partial cross-resistance between PYR/TRM and SDX/SMX (r = 0.85 and 0.65). Correlation was not observed between different dhps genotypes and the in vitro outcome to SDX and SMX (r = 0.30 and 0.34). The lack of correlation could be due to folates and para-aminobenzoic acid in the RPMI medium and the serum used to supplement the cultures.
Khalil
Insaf
I
Center for Medical Parasitology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Panum Institute, Denmark. InsafK@hotmail.com
Rønn
Anita M
AM
Alifrangis
Michael
M
Gabar
Haytham A
HA
Satti
Gwiria M H
GM
Bygbjerg
Ib C
IC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002648:Child; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008875:Middle Aged; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D017354:Point Mutation; D011739:Pyrimethamine / Q000494:pharmacology; D015203:Reproducibility of Results; D013413:Sulfadoxine / Q000494:pharmacology; D013420:Sulfamethoxazole / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D014295:Trimethoprim / Q000494:pharmacology; D014296:Trimethoprim Resistance / Q000235:genetics
D000962:Antimalarials; D013413:Sulfadoxine; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D013420:Sulfamethoxazole; D011739:Pyrimethamine