Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Science. 2011 Aug 5;333(6043):724-9. doi: 10.1126/science.1205216.
Malaria remains a devastating disease largely because of widespread drug resistance. New drugs and a better understanding of the mechanisms of drug action and resistance are essential for fulfilling the promise of eradicating malaria. Using high-throughput chemical screening and genome-wide association analysis, we identified 32 highly active compounds and genetic loci associated with differential chemical phenotypes (DCPs), defined as greater than or equal to fivefold differences in half-maximum inhibitor concentration (IC(50)) between parasite lines. Chromosomal loci associated with 49 DCPs were confirmed by linkage analysis and tests of genetically modified parasites, including three genes that were linked to 96% of the DCPs. Drugs whose responses mapped to wild-type or mutant pfcrt alleles were tested in combination in vitro and in vivo, which yielded promising new leads for antimalarial treatments.
疟疾仍然是一种毁灭性疾病，主要是因为广泛的药物耐药性。新的药物和更好地了解药物作用和耐药性的机制对于实现消除疟疾的承诺至关重要。我们使用高通量化学筛选和全基因组关联分析，鉴定出 32 种与化学表型差异（DCP）相关的高度活性化合物和遗传基因座，定义为寄生虫系之间半最大抑制剂浓度（IC（50））差异大于或等于五倍。通过连锁分析和对遗传修饰寄生虫的测试，确认了与 49 个 DCP 相关的染色体基因座，包括与 96%的 DCP 相关的三个基因。将药物反应映射到野生型或突变型 pfcrt 等位基因的药物在体外和体内进行联合测试，为抗疟治疗提供了有希望的新线索。
