THE PFMDR1 GENE OF PLASMODIUM-FALCIPARUM CONFERS CELLULAR-RESISTANCE TO ANTIMALARIAL-DRUGS IN YEAST-CELLS

The exact rule 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 tr ansporters that includes the mammalian P-glycoprotein family. We have introduced wild-type and mutant variants of the pfmdr1 gene in the yea st Saccharomyces cerevisiae and have analyzed the effect of pfmdr1 exp ression on cellular resistance to quinoline-containing antimalarial dr ugs. Yeast transformants expressing either wild-type or a mutant varia nt of mouse P-glycoprotein were also analyzed. Dose-response studies s howed that expression of wild-type pfmdr1 causes cellular resistance t o quinine, quinacrine, mefloquine, and halofantrine in yeast cells. Us ing quinacrine as substrate, we observed that increased resistance to this drug in pfmdr1 transformants was associated with decreased cellul ar accumulation and a concomitant increase in drug release from preloa ded cells. The introduction of amino acid polymorphisms in TM11 of Pgh -1 (pfmdr1 product) associated with drug resistance in certain field i solates of P. falciparum abolished the capacity of this protein to con fer drug resistance. Thus, these findings suggest that Pgh-1 may act a s a drug transporter in a manner similar to mammalian P-glycoprotein a nd that sequence variants associated with drug-resistance pfmdr1 allel es behave as loss of function mutations.