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

简介：NIAID针对A-C类毒剂的生物防御研究议程已经确定了需要一种 更广泛、更强大的抗感染药物武器库。从以下方面考虑，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，项目二.A.2是由于缺乏对类别生理学的关键方面的了解而产生的 A-C病原体，这是产品开发的基础。在这个项目中，我们将专注于：1)A 不同病原菌的异戊烯基二磷酸生物合成酶与最终产物的比较 目的是开发高通量筛选的分析方法，以识别具有潜在的 发展成为新的治疗方法。2)炭疽芽孢杆菌细胞壁合成的基础生物学 重点鉴定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 本提案中所描述的。本项目(II.A.2)的项目负责人是Dean Crick博士和Patrick博士 布伦南。核心III.C(斯莱登)将提供HTS筛查设施，进入化合物图书馆和 微阵列。CORE III.D(Robison)将提供细菌菌株，用于“Hit化合物”测试。我们会 与项目II C(VASIL)相互作用，在细胞内模型和项目II A3中测试化合物的有效性 (Belisle)以测试复方对图拉氏方济氏菌的药效。还将与以下人员进行密切互动 项目二.A.4(Schweizer)。我们寻找新抗生素类别的方法将与 Schweizers寻找抑制外排泵的化合物。因此，我们的点击率可以进行测试 “可泵性”和与抑制外排泵的化合物的协同作用。

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.