The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.
The exact role of the pfmdr1 gene in the emergence of drug resistance in the malarial parasite Plasmodium falciparum remains controversial. pfmdr1 is a member of the ATP binding cassette (ABC) superfamily of transporters that includes the mammalian P-glycoprotein family. We have introduced wild-type and mutant variants of the pfmdr1 gene in the yeast Saccharomyces cerevisiae and have analyzed the effect of pfmdr1 expression on cellular resistance to quinoline-containing antimalarial drugs. Yeast transformants expressing either wild-type or a mutant variant of mouse P-glycoprotein were also analyzed. Dose-response studies showed that expression of wild-type pfmdr1 causes cellular resistance to quinine, quinacrine, mefloquine, and halofantrine in yeast cells. Using quinacrine as substrate, we observed that increased resistance to this drug in pfmdr1 transformants was associated with decreased cellular accumulation and a concomitant increase in drug release from preloaded cells. The introduction of amino acid polymorphisms in TM11 of Pgh-1 (pfmdr1 product) associated with drug resistance in certain field isolates of P. falciparum abolished the capacity of this protein to confer drug resistance. Thus, these findings suggest that Pgh-1 may act as a drug transporter in a manner similar to mammalian P-glycoprotein and that sequence variants associated with drug-resistance pfmdr1 alleles behave as loss of function mutations.
Ruetz
S
S
Department of Biochemistry, McGill University, Montreal, QC Canada.
Delling
U
U
Brault
M
M
Schurr
E
E
Gros
P
P
D018528:ATP-Binding Cassette Transporters; D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D015767:Mefloquine / Q000494:pharmacology; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000235:genetics*; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics* / Q000502:physiology; D011796:Quinacrine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D010616:Phenanthrenes; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D011803:Quinine; D011796:Quinacrine; C023768:halofantrine; D015767:Mefloquine