The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand.
On the western border of Thailand, Plasmodium falciparum has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the pfmdr1 gene in 54 parasites collected from the western border of Thailand to determine the relationship of pfmdr1 copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC(50)) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86. Increased pfmdr1 copy number was associated with higher IC(50)s of mefloquine (P = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.
Price
R N
RN
Department of Infectious Diseases, St. George's Hospital Medical School, London, United Kingdom.
Cassar
C
C
Brockman
A
A
Duraisingh
M
M
van Vugt
M
M
White
N J
NJ
Nosten
F
F
Krishna
S
S
D018528:ATP-Binding Cassette Transporters; D000483:Alleles; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics; D000962:Antimalarials / Q000494:pharmacology*; D003062:Codon / Q000235:genetics; D016054:DNA, Protozoan / Q000032:analysis / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D018628:Gene Dosage; D005819:Genetic Markers; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D015767:Mefloquine / Q000494:pharmacology; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects*; D011110:Polymorphism, Genetic / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013785:Thailand
D018528:ATP-Binding Cassette Transporters; D000953:Antigens, Protozoan; D000962:Antimalarials; D003062:Codon; D016054:DNA, Protozoan; D005819:Genetic Markers; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; C065974:merozoite surface protein 2, Plasmodium; D015767:Mefloquine