Isoprenoid Biosynthesis: A Target for Drugs Against Category A-C Pathogens

类异戊二烯生物合成：A-C 类病原体药物的靶标

• 批准号: 7641021
• 负责人: DEAN C CRICK
• 金额: $ 23.87万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641021
• 关键词: Anabolism; Anthrax disease; Anti-Infective Agents; Antibiotics; Bacillus (bacterium); Bacillus anthracis; Biological Assay; Biology; Bioterrorism; Categories; Cell Wall; Cell surface; Cells; Class; Core Facility; Development; Drug Delivery Systems; Elements; Enzymes; Facility Accesses; Francisella tularensis; Genomics; Genus Mycobacterium; Heel; Immunology; Kinetics; Knowledge; Libraries; Light; Lipids; Mission; Modeling; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Organism; Pathway interactions; Peptidoglycan; Pharmaceutical Preparations; Physiology; Play; Polymers; Polysaccharides; Research; Role; Screening procedure; Structure; Teichoic Acids; Testing; Tuberculosis; Vaccines; Validation; Virulence; Work; biodefense; cell envelope; chemotherapy; drug development; efflux pump; expression cloning; genetic manipulation; high throughput screening; indolepropanol phosphate; isopentenyl pyrophosphate; isoprenoid; lipoteichoic acid; mevalonate; novel therapeutics; pathogen; programs; response; teichuronic acid

Introduction: The NIAID biodefense research agendas for category A-C agents have identified a need for a broader, more robust arsenal of anti-infective agents. This is important when considered in the light of recent research in genomics and immunology which has greatly eased the task of genetic manipulation of pathogens. Thus, Project II.A.2 arises from the lack of knowledge of key aspects of physiology of Category A-C pathogens which is fundamental to product development. In this project we will concentrate on: 1) A comparison of isopentenyl diphosphate biosynthetic enzymes from a variety of pathogens with the ultimate aim of developing assays for high throughput screening in order to identify compounds that have potential for development into novel therapeutics. 2) the basic biology of cell wall synthesis in Bacillus anthacis, with emphasis on identifying anionic polysaccharides and the "linker-unit" of the organism, polysaccharide biosynthetic pathways and specific drug target identification. Project interactions: This project will be closely integrated with the other projects and Core Facilities described in this proposal. The Project Leaders of this project (II.A.2) are Drs. Dean Crick and Patrick Brennan. Core III.C (Slayden) will provide HTS screening facilities, access to compound libraries and microarrays. Core III.D (Robison) will provide bacterial strains for testing with "hit compounds". We will interact with Project II.C (Vasil) to test efficacy of compounds in intracellular models and Project II A3 (Belisle) to test compound efficacy against Francisella tularensis. There will also be close interactions with Project II.A.4 (Schweizer). Our approach of looking for new antibiotic classes will synergize with Schweizers's search for compounds which inhibit efflux pumps. Thus, our hits can be tested for "pumpability" and synergy with compounds that inhibit efflux pumps.

简介：NIAID 针对 A-C 类制剂的生物防御研究议程已确定需要 更广泛、更强大的抗感染药物库。考虑到这一点很重要 基因组学和免疫学的最新研究极大地简化了基因操作的任务 病原体。因此，项目 II.A.2 源于对类别生理学关键方面知识的缺乏 A-C 病原体是产品开发的基础。在这个项目中，我们将重点关注：1）A 多种病原体的异戊烯二磷酸生物合成酶与最终结果的比较 开发高通量筛选分析方法的目的是为了识别具有潜力的化合物 开发成新疗法。 2) 炭疽杆菌细胞壁合成的基础生物学， 强调识别阴离子多糖和生物体的“连接单元”，多糖 生物合成途径和特定药物靶点识别。 项目互动：该项目将与其他项目和核心设施紧密结合 本提案中描述。该项目（II.A.2）的项目负责人是博士。迪恩·克里克和帕特里克 布伦南。 Core III.C (Slayden) 将提供 HTS 筛选设施、化合物库的访问和 微阵列。 Core III.D (Robison) 将提供用于测试“命中化合物”的细菌菌株。我们将 与 Project II.C (Vasil) 相互作用，测试化合物在细胞内模型和 Project II A3 中的功效 （Belisle）测试化合物对土拉弗朗西斯菌的功效。还将与大家进行密切互动 项目 II.A.4 (Schweizer)。我们寻找新抗生素类别的方法将与 施韦泽尔正在寻找抑制外排泵的化合物。因此，我们的点击可以被测试 “泵送性”以及与抑制外排泵的化合物的协同作用。