A strong association between mefloquine and halofantrine resistance and amplification, overexpression, and mutation in the P-glycoprotein gene homolog (pfmdr) of Plasmodium falciparum in vitro.
Stepwise selection for increased mefloquine resistance in a line of Plasmodium falciparum in vitro resulted in increased resistance to halofantrine and quinine, increased sensitivity to chloroquine, and amplification and overexpression of the P-glycoprotein gene homolog (pfmdr1). A point mutation (tyrosine to phenylalanine) noted at amino acid 86 in pfmdr1 in the mefloquine-resistant line W2mef was amplified in more resistant lines derived from it by in vitro selection pressure with mefloquine. Conversely, lines selected for increased chloroquine resistance exhibited a revertant phenotype that was sensitive to mefloquine and halofantrine. These lines also demonstrated increased sensitivity to quinine, loss of amplification of pfmdr1, loss of the mefloquine/halofantrine phenylalanine-86 mutation, and selection for a tyrosine-86 mutation previously associated with chloroquine resistance. These findings provide strong evidence for pfmdr1 mediating cross-resistance to halofantrine and mefloquine in P. falciparum in vitro.
Peel
S A
SA
Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill.
Bright
P
P
Yount
B
B
Handy
J
J
Baric
R S
RS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D002738:Chloroquine / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D016054:DNA, Protozoan / Q000737:chemistry; D004351:Drug Resistance / Q000235:genetics; D005784:Gene Amplification; D015870:Gene Expression; D017125:Genes, Protozoan; D015767:Mefloquine / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010616:Phenanthrenes / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011803:Quinine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012641:Selection, Genetic; D012689:Sequence Homology, Nucleic Acid; D012717:Sesquiterpenes / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D037621:Artemisinins; D017931:DNA Primers; D016054:DNA, Protozoan; D010616:Phenanthrenes; D012333:RNA, Messenger; D012717:Sesquiterpenes; D002738:Chloroquine; C031327:artemisinin; D011803:Quinine; C023768:halofantrine; D015767:Mefloquine