Plasmodium falciparum: amplification and overexpression of pfmdr1 is not necessary for increased mefloquine resistance.
Amplification and overexpression of the pfmdr1 gene has been associated with mefloquine resistance in Plasmodium falciparum. We have selected for parasites more resistant to mefloquine from P. falciparum FAC8, a clone that has three copies of pfmdr1. The parasite lines derived from this selection were up to threefold more resistant to mefloquine. The mefloquine-selected parasites were also more resistant to quinine and halofantrine, suggesting a multidrug resistance phenotype. In contrast to previous findings, the selection of P. falciparum FAC8 on mefloquine did not alter the copy number or the level of expression of pfmdr1. Sequence analysis of pfmdr1 from the selected lines showed no change in the amino acids. These results show that alterations in pfmdr1 are not involved in mediating the increased mefloquine resistance observed in this clone.
Lim
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AS
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Galatis
D
D
Cowman
A F
AF
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D016054:DNA, Protozoan / Q000032:analysis / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D005784:Gene Amplification; D018628:Gene Dosage; D005786:Gene Expression Regulation; D017125:Genes, Protozoan; D015767:Mefloquine / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000032:analysis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014700:Verapamil / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D016054:DNA, Protozoan; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D014700:Verapamil; D015767:Mefloquine