title: pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum.
abstract: Efforts to control malaria worldwide have been hindered by the development and expansion of parasite populations resistant to many first-line antimalarial compounds. Two of the best-characterized determinants of drug resistance in the human malaria parasite Plasmodium falciparum are pfmdr1 and pfcrt, although the mechanisms by which resistance is mediated by these genes is still not clear. In order to determine whether mutations in pfmdr1 associated with chloroquine resistance affect the capacity of the parasite to persist when drug pressure is removed, we conducted competition experiments between P. falciparum strains in which the endogenous pfmdr1 locus was modified by allelic exchange. In the absence of selective pressure, the component of chloroquine resistance attributable to mutations at codons 1034, 1042 and 1246 in the pfmdr1 gene also gave rise to a substantial fitness cost in the intraerythrocytic asexual stage of the parasite. The loss of fitness incurred by these mutations was calculated to be 25% with respect to an otherwise genetically identical strain in which wild-type polymorphisms had been substituted at these three codons. At least part of the fitness loss may be attributed to a diminished merozoite viability. These in vitro results support recent in vivo observations that in several countries where chloroquine use has been suspended because of widespread resistance, sensitive strains are re-emerging.
authors.affiliation: School of Biochemistry and Molecular Biology, Faculty of Science, The Australian National University, Canberra ACT 0200, Australia.
authors.forename: Rhys
authors.initials: R
authors.lastname: Hayward
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Saliba
authors.forename: Kiaran
authors.initials: K
authors.lastname: Kirk
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001483:Base Sequence; D002738:Chloroquine / Q000494:pharmacology*; D017931:DNA Primers; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D017931:DNA Primers; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine