MEP pathway 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健康的严重威胁， 每年有一百万人死亡由于对现有抗疟药物的广泛耐药性， 治疗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， 在人类中是找不到的。我们已经使用正向遗传筛选来鉴定疟疾寄生虫的抗药性 MEP通路抑制。因此，我们确定了一个新的疟疾代谢调节因子家族， 有蛋白质。我们现在建议确定HAD磷酸酶的损失的机制， 赋予抗药性（目标1）;确定HADs在寄生虫发育中的生物学功能 (Aim 2）;并使用新的MEP通路抑制剂来鉴定和表征 阻力（目标3）。我们将鉴定恶性疟原虫基因和与恶性疟原虫基因相互作用的途径。 重要的MEP途径和我们强有力的初步结果支持这种方法。此外，我们的结果 将告知我们对代谢调节剂的HAD家族的基础生物学的理解，并将 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.