Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
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.
Yuan
Jing
J
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
Johnson
Ronald L
RL
Huang
Ruili
R
Wichterman
Jennifer
J
Jiang
Hongying
H
Hayton
Karen
K
Fidock
David A
DA
Wellems
Thomas E
TE
Inglese
James
J
Austin
Christopher P
CP
Su
Xin-zhuan
XZ
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D004087:Dihydroergotamine