title: Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
abstract: Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wichterman
authors.forename: Hongying
authors.initials: H
authors.lastname: Jiang
authors.forename: Karen
authors.initials: K
authors.lastname: Hayton
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wellems
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Xin-zhuan
authors.initials: XZ
authors.lastname: Su
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004087:Dihydroergotamine / Q000494:pharmacology; D015195:Drug Design; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D040641:Quantitative Trait Loci; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D004087:Dihydroergotamine