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HTS assays for the methylerythritol-4-phosphate pathway

4-甲基赤藓糖醇-4-磷酸途径的 HTS 测定

基本信息

批准号：
8459369
负责人：
DEAN C CRICK
金额：
$ 35.29万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459369
关键词：
Anabolism Antibiotics Antitubercular Agents Area Attention Bacteria Biochemical Biological Assay Carboxy-Lyases Cells Clinical Communities Development Diphosphates Drug Design Drug Resistant Tuberculosis Drug Targeting Engineering Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Eukaryotic Cell Extreme drug resistant tuberculosis Genes Genome Genus Mycobacterium Goals Gram-Negative Bacteria Growth Human Incidence International Knowledge Laboratories Lead Mevalonate kinase Multidrug-Resistant Tuberculosis Mus Mycobacterium tuberculosis NIH Program Announcements Operon Orthologous Gene Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phosphomevalonate kinase Physiological Plasmodium Property Proteins Reaction Role Running Series Solutions Source Testing Therapeutic Toxic effect Toxoplasma Tuberculosis Work Yeasts antimicrobial base drug development enzyme pathway fosmidomycin genetic evolution high throughput screening in vivo inhibitor/antagonist inorganic phosphate interest isopentenyl pyrophosphate isoprenoid killings mevalonate novel pathogen pathogenic bacteria programs response screening small molecule tool tuberculosis drugs tuberculosis treatment working group

项目摘要

This proposal is based on studies of the methylerythritol-4-phosphate (MEP) pathway that synthesizes the universal precursors of isoprenoid compounds, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), in which we have identified potential drug targets in Mycobacterium tuberculosis and other bacterial pathogens. These targets also exist in Plasmodium and Toxoplasma species. The enzymes involved in the MEP pathway in pathogenic bacteria have recently generated a great deal of attention as a source of targets for novel antimicrobials; all enzymes in the MEP pathway are thought to be potential targets for novel drugs as the MEP pathway has been demonstrated to be essential in both Gram-positive and Gram-negative bacteria and human cells do not contain orthologs. In addition, a natural antibiotic, fosmidomycin, which inhibits the second enzyme in the pathway (IspC) also inhibits the growth of Gram-negative bacteria and we have shown that inhibitors of the first enzyme in the MEP pathway (Dxs) also inhibits the growth of M. tuberculosis. However, few laboratories have been able to pursue this topic in detail due to a lack of substrates and appropriate HTS amenable assays. Our previous work in this area was aimed at characterizing MEP pathway enzymes from bacterial pathogens and developing efficient syntheses for the substrates; our present goal is to identify and develop inhibitors of previously characterized enzymes to provide potential leads for development of novel antimicrobial compounds.

这一提议是基于对合成多聚体的甲基-4-磷酸（MEP）途径的研究。类异戊二烯化合物的通用前体，异戊烯基二磷酸（IPP）和二甲基烯丙基二磷酸（DMAPP），其中我们已经确定了结核分枝杆菌和其他细菌中的潜在药物靶点病原体这些靶标也存在于疟原虫和弓形虫物种中。参与蛋白质合成的 MEP途径作为病原菌的一个来源靶点，近年来引起了人们的极大关注 MEP途径中的所有酶都被认为是新型药物的潜在靶点， MEP途径已被证明在革兰氏阳性菌和革兰氏阴性菌中都是必需的而人类细胞不含直系同源物。此外，一种天然抗生素，磷霉素，它抑制了途径中的第二种酶（IspC）也抑制革兰氏阴性菌的生长，我们已经证明 MEP途径中的第一种酶（Dxs）的抑制剂也抑制M的生长。结核然而，由于缺乏底物，适当的HTS适用测定。我们以前在这一领域的工作旨在表征MEP途径酶从细菌病原体和开发有效的合成底物;我们目前的目标是鉴定和开发先前表征酶的抑制剂，为开发提供潜在线索新的抗菌化合物。