RETRACTED: The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.

Abstract

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.

Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

“…Transformation studies in yeast have shown that pfmdr1 expression results in a reduced sensitivity to MQ and HF whereas expression of a mutant pfmdr1 (carrying two of the three 7G8 mutations) did not. 25 These observations would support the observations reported here.…”

“…15 Interestingly, it is this 7G8 mutation that has been used in the limited transformation studies that have been carried out to date and which support a role for pfmdr1 in resistance. 25,42 One biochemical characteristic that does appear to be associated with CQ resistance in all isolates studied, irrespective of origin, is the ability of verapamil to selectively chemosensitize resistant isolates. 12,43,44 All of the new isolates studied here retained this phenotypic characteristic, including those with intermediate sensitivity.…”

“…20,21 A role for pfmdr1 has been suggested as the basis for MQ and HF resistance, 17,19,22 and as with CQ resistance, this view remains controversial. Drug pressure experiments in laboratory isolates [22][23][24] and the transfection of pfmdr1 into yeast 25 have been presented as evidence in support of a role of overexpression of pfmdr1 in MQ and HF resistance. However other studies provide compelling evidence against this association.…”

Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.

“…28 In addition, Pgh-1 expression in yeast cells confers cellular resistance to mefloquine, quinine, halofantrine, and quinacrine. 33 If one considers that CQ resistance originated almost simultaneously in Southeast Asia and South America, it is possible that this phenomenon involves multiple transport mechanisms and multiple genes. Recently, field studies 34 have identified a series of mutations of the cg2 gene in CQ resistant P. falciparum, suggesting that this gene is also involved.…”

Molecular epidemiology of malaria in Yaounde, Cameroon V. analysis of the omega repetitive region of the plasmodium falciparum CG2 gene and chloroquine resistance.

“…9,10 Although the pfmdr 1 gene, but not pfmdr 2, codes for a transmembrane protein capable of transporting drugs across the membrane and point mutations may alter its function, its role in resistance to 4-aminoquinolines and aminoalcohols is still unclear. [11][12][13] A second candidate, cg2 gene, has been recently isolated and characterized. 14 Its functional role is currently unknown.…”