MEP pathway 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健康构成严重威胁 每年有一百万人死亡。由于对现有疟疾药物的广泛耐药性，需要新的抗疟疾药物 治疗。一个有前景的抗疟疾药物靶点是类异戊二烯生物合成的MEP途径，它 在人类身上找不到。我们已经使用正向基因筛查来鉴定抗药性疟疾寄生虫。 对MEP通路的抑制。因此，我们已经确定了疟疾中的一个新的代谢调节因子家族，即 含有蛋白质。我们现在建议确定HAD磷酸酶丢失的机制 赋予抗药性(目标1)；建立HADS在寄生虫发育中的生物学功能 (目标2)；并使用一种新的MEP途径抑制剂来识别和表征其他机制 抵抗(目标3)。我们将确定恶性疟原虫基因和途径，这些基因和途径与恶性疟原虫 Essential MEP途径和我们强有力的初步结果支持这一方法。另外，我们的结果是 将有助于我们对代谢调节剂HAD家族的基本生物学的理解 确定HAD介导的耐药性是否可以传播。

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. We have used forward genetic screening to identify malaria parasites resistant to MEP pathway inhibition. We have thus identified a new family of metabolic regulators in malaria, the HAD proteins. We now propose to determine the mechanism by which loss of HAD phosphatases confers drug resistance (Aim 1); establish the biological functions of HADs in parasite development (Aim 2); and use a new MEP pathway inhibitor to identify and characterize additional mechanisms of resistance (Aim 3). We will identify P. falciparum genes and pathways that genetically interact with the essential MEP pathway and our strong preliminary results support this approach. In addition, our results will inform our understanding of the basic biology of the HAD family of metabolic regulators and will determine whether HAD-mediated drug resistance can be transmitted.