Novel Therapeutics for Bacillus anthracis

描述(申请人提供)：开发抗药性炭疽杆菌菌株在技术上是相当可行的，并可能在未来的恐怖袭击中构成重大威胁。在参与该项目的研究人员之间建立良好的合作网络的基础上，我们提出了一种综合的方法来开发新的抗菌剂、现有抗菌剂的新增强剂和炭疽毒素的直接抑制剂，以此作为对抗自然和生物工程炭疽杆菌的战略。我们将使用一系列策略，首先是新细菌靶标的遗传鉴定和验证，确定靶标3D分子结构，利用不同的化学库进行高通量筛选，基于结构的药物设计，先导化合物的合成和优化，然后是巨噬细胞和动物试验。应用的一个重要优势是参与者的广泛专业知识，包括细菌遗传学和生物化学、大分子结构生物学、计算机辅助药物设计、合成化学、巨噬细胞生物学、动物建模和临床传染病。项目1将识别和验证核糖体RNA中的新抗生素靶点。项目2将确定和验证炭疽芽孢杆菌感染相关的新靶点。项目3将利用基于结构的设计和高通量筛选来开发目前已知和待确定的抗生素靶点的先导抑制剂。项目4将开发抑制物来阻止炭疽杆菌毒素与细胞受体的结合。项目5将评估抗生素在巨噬细胞感染和动物模型发展后调节细胞因子激活和毒素触发方面的作用。四个科学核心将支持这些项目：一个蛋白质表达核心将为目标评估和基于结构的设计提供蛋白质。大分子表征和结构核将为靶标表征和基于结构的设计提供结构和热力学信息。化学改进核心将提供铅缓蚀剂的合成设计和优化。生物检测核心将为识别和评估铅治疗剂提供各种检测方法。行政核心将提供财政管理和行政支助。

DESCRIPTION (provided by applicant): The development of drug-resistant strains of B. anthracis is technically quite feasible, and could be a substantial threat in future terrorist attacks. Building on a well-established collaborative network amongst the investigators participating in this project, we propose an integrated approach toward the development of new antimicrobials, new potentiators of existing antimicrobials, and direct inhibitors of the anthrax toxin as strategies to combat natural and bioengineered forms of B. anthracis. We will use a combination of strategies, beginning with genetic identification and validation of novel bacterial targets, determination of target 3D molecular structures, utilization of diverse chemical libraries for high throughput screening, structure-based drug design, synthesis of lead compounds and their optimization, followed by macrophage and animal testing. An important strength of the application is the broad range of the participants' expertise, including bacterial genetics and biochemistry, structural biology of macromolecules, computer-assisted drug design, synthetic chemistry, macrophage biology, animal modeling and clinical infectious disease. Project 1 will identify and validate new antibiotic targets in ribosomal RNA. Project 2 will identify and validate new infection-related targets in Bacillus anthracis. Project 3 will utilize structure-based design and high throughput screening to develop lead inhibitors of currently known and to-be-identified antibiotic targets. Project 4 will develop inhibitors to prevent the binding of the B. anthracis toxin to the cellular receptor. Project 5 will evaluate the role of antibiotics in modulating cytokine activation and toxin triggering following macrophage infection and animal model development. Four scientific cores will support these projects: A protein expression core will provide proteins for target evaluation and structure-based design. A macromolecular characterization and structure core will provide structural and thermodynamic information for target characterization and structure-based design. A chemical improvement core will provide synthetic design and optimization of lead inhibitors. A bioassay core will provide a variety of assays for identifying and evaluating lead therapeutic agents. An administrative core will provide fiscal management and administrative support.