FOSMIDOMYCIN RESISTANCE IN PLASMODIUM FALCIPARUM

项目总结 由恶性疟原虫感染引起的严重疟疾对全球构成严重威胁 每年有100多万人死于健康问题。由于以下原因需要新的抗疟疾药物 对现有疗法的广泛抵抗。一个很有希望的抗疟疾药物靶点是 类异戊二烯生物合成的MEP途径，这在人类中没有发现。这条路是 目前处于II期临床的抗疟疾药物磷霉素的靶点 疟疾联合疗法的试验。我们已经使用了正向基因筛查来 鉴定耐磷霉素性疟疾寄生虫，以调查其基因 提高对磷霉素类抗生素耐药机制的认识 类异戊二烯生物学。因此，我们已经确定了一个新的代谢调节家族 疟疾，HAD蛋白质。我们的方针包括两个具体目标：(1)建立 HAD介导的耐药机制，以及(2)基因和 缺乏疟疾菌株耐药性增强的代谢机制 哈兹。我们将确定恶性疟原虫的基因和与之相互作用的途径 必要的MEP途径和我们强有力的初步结果支持这一方法。 我们的结果将识别磷霉素类耐药性的分子生物标记物，并识别 迫切需要的抗疟疾药物开发的新目标。

Project summary Severe malaria due to infection by Plasmodium falciparum is a serious threat to global health with over a million deaths per year. New antimalarial agents are needed due to widespread resistance to existing therapies. A promising antimalarial drug target is the MEP pathway of isoprenoid biosynthesis, which is not found in humans. This pathway is the target of an antimalarial agent, fosmidomycin, which is currently in Phase II clinical trials in combination therapies for malaria. We have used forward genetic screening to identify fosmidomycin-resistant malaria parasites, in order to investigate the genetic mechanisms of fosmidomycin resistance and advance our basic understanding of isoprenoid biology. We have thus identified a new family of metabolic regulators in malaria, the HAD proteins. Our approach consists of two specific aims: (1) Establish the mechanisms of HAD-mediated drug resistance, and (2) Characterize the genetic and metabolic mechanisms that underlie enhanced drug resistance in malaria strains lacking HADs. We will identify P. falciparum genes and pathways that genetically interact with the essential MEP pathway and our strong preliminary results support this approach. Our results will identify molecular biomarkers of fosmidomycin resistance and identify new targets for much needed antimalarial drug development.