BIOORGANIC CHEMISTRY OF ANTIBACTERIALS

抗菌剂的生物有机化学

• 批准号: 6170703
• 负责人: MICHAEL C PIRRUNG
• 金额: $ 19.87万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170703
• 关键词: alginates; arabinose; biochemistry; chemical registry /resource; chemical structure function; chemical synthesis; combinatorial chemistry; drug design /synthesis /production; drug resistance; endotoxins; enzyme activity; ethambutol; metalloendopeptidases; microorganism culture; naphthoquinones; protein kinase; transferase; vancomycin

The long term goal of this research is to develop novel anti-infective disease agents using rational drug design and combinatorial chemistry. The broad objectives of this program are the development of novel antibacterial agents that will address issues of drug resistance. The narrow objectives of the several projects are: discovery of inhibitors of the microbial histidine-aspartate kinase two-component signaling system that is responsible for vancomycin resistance; discovery of inhibitors of a metallopeptidase involved in lipid A biosynthesis; discovery of inhibitors of a 3-arabinosyl transferase involve din the biosynthesis of arabinan segments of mycobacterial cell wall. These molecular targets for antibacterial action come from both gram-negative and gram-positive bacteria. One project will also investigate the total synthesis on sold phase of molecules that exhibit strong anti-infective activity, butt whose molecular targets are not known. Methods to prepare combinatorial libraries of these materials for the discovery of more potent or different antibacterial actions will then be developed. An additional project will involved a "generic" combinatorial library that can be used to map space in active sites of novel protein targets derived from microbial pathogens, allowed integration of combinatorial techniques and rational design principles. One particularly valuable aspect of this work will be the development of a new combinatorial library tagging methodology that permits rapid identification of molecules by NMR. This project will utilize the methods of organic synthesis on the solid phase, combinatorial chemistry, and antibacterial screening. This research will be significant because of the great difficulty medicine now perceives with pathogens that are resistant to conventional antibacterial drugs. Molecules that can modulate signaling events associated with histidine-aspartate kinases would be of great value in both basic scientific investigation and in potential control of microbial physiology and growth. An ancillary benefit of this project will be the development of novel techniques in solid phase synthesis through the total synthesis of natural products.

这项研究的长期目标是发展新型的反感染性 使用合理的药物设计和联合化学的疾病剂。这 该计划的广泛目标是新颖的发展 将解决耐药性问题的抗菌剂。这 几个项目的狭窄目标是：发现的抑制剂 微生物组氨酸 - 天冬氨酸激酶两组分组信号传导系统 负责万古霉素耐药性；发现抑制剂 与脂质A生物合成有关的金属肽酶；发现 3-阿拉伯糖基转移酶的抑制剂涉及DIN的生物合成 分枝杆菌细胞壁的阿拉伯群节。这些分子靶标 抗菌作用来自革兰氏阴性和革兰氏阳性 细菌。一个项目还将调查已销售的总合成 表现出强大抗感染活性的分子的阶段 分子靶标尚不清楚。 准备组合的方法 这些材料的库，以发现更有效或不同 然后将开发抗菌作用。另一个项目将 涉及一个可用于映射空间的“通用”组合库 在来自微生物病原体的新型蛋白质靶点的活跃部位中， 允许整合组合技术和理性设计 原则。这项工作的一个特别有价值的方面将是 开发新的组合库标记方法 允许通过NMR快速鉴定分子。 该项目将利用有机合成的方法 相，组合化学和抗菌筛查。 这项研究将很重要，因为很难医学 现在感知到对常规抗性的病原体 抗菌药物。可以调节信号事件的分子 与组氨酸 - 天冬氨酸激酶有关 基础科学研究和微生物的潜在控制 生理和成长。该项目的辅助好处将是 通过总计开发固相合成中的新技术 天然产物的合成。