Role of pfmdr1 mutations on chloroquine resistance in Plasmodium falciparum isolates with pfcrt K76T from Papua New Guinea.
The N86Y mutation in pfmdr1 is reported to play an additional role for the chloroquine resistance in Plasmodium falciparum isolates. However, not much has been done to clarify whether this mutation augments the level of chloroquine resistance in the isolates harboring pfcrt K76T mutation. We compared the in vitro chloroquine efficacy between pfcrt K76T mutant parasites with or without N86Y mutation from Papua New Guinea. A total of 57 isolates (4% sensitive, 14% borderline, and 82% resistant) were successfully tested in vitro for chloroquine sensitivity. We found a slightly higher effective concentration of chloroquine needed to inhibit P. falciparum by 50% (mean EC50=107 nM) in isolates with the pfcrt K76T+pfmdr1 N86Y than that in isolates with the pfcrt K76T+pfmdr1 N86 (EC50=88 nM), but this difference was not statistically significant. A significant non-random association was observed between the pfcrt K76T and pfmdr1 N86Y alleles. Our results suggest that the pfmdr1 N86Y mutation plays a compensatory role to chloroquine-resistant isolates under a chloroquine pressure while it may also augment the level of chloroquine resistance in the K76T parasites to a small extent.
Mita
Toshihiro
T
Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan. hiro-tm@research.twmu.ac.jp
Kaneko
Akira
A
Hombhanje
Francis
F
Hwaihwanje
Ilomo
I
Takahashi
Nobuyuki
N
Osawa
Hikota
H
Tsukahara
Takahiro
T
Masta
Andrew
A
Lum
Jeffery K
JK
Kobayakawa
Takatoshi
T
Ishizaki
Takashi
T
Björkman
Anders
A
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology*; D016054:DNA, Protozoan / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000469:parasitology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009154:Mutation; D010219:Papua New Guinea; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D016054:DNA, Protozoan; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine