Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents.
Chloroquine resistance in Plasmodium falciparum is primarily conferred by mutations in pfcrt. Parasites resistant to chloroquine can display hypersensitivity to other antimalarials; however, the patterns of crossresistance are complex, and the genetic basis has remained elusive. We show that stepwise selection for resistance to amantadine or halofantrine produced previously unknown pfcrt mutations (including S163R), which were associated with a loss of verapamil-reversible chloroquine resistance. This was accompanied by restoration of efficient chloroquine binding to hematin in these selected lines. This S163R mutation provides insight into a mechanism by which PfCRT could gate the transport of protonated chloroquine through the digestive vacuole membrane. Evidence for the presence of this mutation in a Southeast Asian isolate supports the argument for a broad role for PfCRT in determining levels of susceptibility to structurally diverse antimalarials.
Johnson
David J
DJ
Molecular & Biochemical Parasitology Group, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.
Fidock
David A
DA
Mungthin
Mathirut
M
Lakshmanan
Viswanathan
V
Sidhu
Amar Bir Singh
AB
Bray
Patrick G
PG
Ward
Stephen A
SA
D000409:Alanine / Q000378:metabolism; D000483:Alleles; D000547:Amantadine / Q000378:metabolism / Q000494:pharmacology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D017125:Genes, Protozoan; D006239:Haplotypes; D006427:Hemin / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D021261:Parasitic Sensitivity Tests; D010616:Phenanthrenes / Q000378:metabolism / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D017354:Point Mutation; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins; D011995:Recombination, Genetic; D014700:Verapamil / Q000494:pharmacology
D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D010616:Phenanthrenes; D015800:Protozoan Proteins; D006427:Hemin; D002738:Chloroquine; D000547:Amantadine; D014700:Verapamil; D000409:Alanine; C023768:halofantrine