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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.

SUBMITTER: Yuan J 

PROVIDER: S-EPMC2784992 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.

Yuan Jing J   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  

Nature chemical biology 20090906 10


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 d  ...[more]

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