Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum
Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum
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DOI：
10.1038/nchembio.215
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发表时间：
2009-10-01
影响因子：
14.8
通讯作者：
Su, Xin-zhuan
中科院分区：
文献类型：
--
作者：
Yuan, Jing;Johnson, Ronald L.;Su, Xin-zhuan
恶性疟原虫基因功能和分子机制的研究受到个体间表型差异表征和测量困难的阻碍。我们筛选了7个寄生虫品系对1,279种生物活性化学物质的反应差异。数百种化合物具有抑制寄生虫生长的活性；共编目了607种不同化学表型，定义为寄生虫品系间IC50的成对差异为5倍或更多。我们绘制了一个遗传杂交亲本之间三种差异化学表型的主要决定因素，并通过精细定位和测试候选基因被突变等位基因遗传取代的寄生虫的反应来确定目标基因。对血清素受体拮抗剂二氢麦角胺甲磺酸盐(1)的差异敏感性被定位到一个编码人类p -糖蛋白（pfgh -1）同源基因。本研究确定了抗疟疾药物的新线索，并证明了高通量化学基因组策略在研究疟疾性状方面的实用性。
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 IC50 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.