FOSMIDOMYCIN RESISTANCE IN PLASMODIUM FALCIPARUM

项目摘要 由恶性疟原虫感染引起的严重疟疾是对全球的严重威胁。 每年有超过一百万人死亡。需要新的抗疟疾药物， 对现有疗法的广泛耐药性。一个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，在人类中没有发现。该途径 抗疟药磷咪霉素的靶点，目前正处于II期临床阶段 疟疾联合疗法的试验。我们已经使用了遗传筛查， 确定对膦咪霉素耐药的疟原虫，以研究其遗传学特性。 磷司米霉素耐药机制的研究进展， 类异戊二烯生物学因此，我们确定了一个新的代谢调节因子家族， 疟疾，HAD蛋白。我们的方法包括两个具体目标：（1）建立 HAD介导的耐药机制，和（2）表征遗传和 在缺乏抗疟疾药物的疟疾菌株中增强抗药性的代谢机制 HAD。我们将确定恶性疟原虫基因和途径，遗传相互作用， 重要的MEP途径和我们强有力的初步结果支持这种方法。 我们的研究结果将确定磷霉素耐药性的分子生物标志物， 急需的抗疟药物开发的新目标。

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.