FOSMIDOMYCIN RESISTANCE IN PLASMODIUM FALCIPARUM

恶性疟原虫对磷米霉素的耐药性

• 批准号: 10058237
• 负责人: Audrey Ragan Odom John
• 金额: $ 42.3万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058237
• 关键词: Anabolism; Antimalarials; Biological Process; Biology; Carbon; Catalysis; Cells; Cessation of life; Chemicals; Combined Modality Therapy; Data; Development; Drug Targeting; Drug resistance; Enzymes; Eubacterium; Family; Future; Genes; Genetic; Genetic Screening; Glycolysis; Goals; Growth; Homeostasis; Human; Infection; Investigation; Life; Malaria; Mediating; Metabolic; Metabolic Control; Metabolism; Molecular; Nucleotidases; Organism; Parasites; Pathway interactions; Phase II Clinical Trials; Phosphoric Monoester Hydrolases; Phosphorylation; Plants; Plasmodium falciparum; Protein Dephosphorylation; Proteins; Regulation; Resistance; Role; Structure; Substrate Specificity; Transgenic Organisms; Variant; base; clinical development; drug development; drug metabolism; fosmidomycin; genetic approach; global health; improved; inhibitor/antagonist; innovation; isoprenoid; metabolomics; molecular marker; mutant; next generation sequencing; novel therapeutics; pathogen; sugar; sugar-phosphatase; tool

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.

项目概要 恶性疟原虫感染引起的严重疟疾对全球构成严重威胁 每年造成超过一百万人死亡。由于以下原因需要新的抗疟药物 对现有疗法的广泛耐药性。一个有前景的抗疟药物靶点是 类异戊二烯生物合成的 MEP 途径，在人类中未发现。这条途径是 抗疟药 Fosmidomycin 的靶标，目前处于 II 期临床 疟疾联合疗法的试验。我们使用正向基因筛查来 鉴定对磷米霉素具有抗药性的疟疾寄生虫，以研究遗传性 磷米霉素耐药机制并增进我们的基本了解 类异戊二烯生物学。因此，我们发现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，以及 (2) 表征遗传和 疟疾菌株耐药性增强的代谢机制缺乏 HAD。我们将鉴定恶性疟原虫基因和与以下基因相互作用的途径： MEP 的基本途径和我们强有力的初步结果支持了这一方法。 我们的结果将鉴定磷米霉素耐药性的分子生物标志物并确定 急需的抗疟药物开发的新目标。