Identification of small molecule inhibitors of the capsule synthesis of gram-negative bacteria

革兰氏阴性菌荚膜合成小分子抑制剂的鉴定

• 批准号: 10005005
• 负责人: Matthew Hall
• 金额: $ 13.27万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10005005
• 关键词: Antibiotics; Antibodies; Award; Bacteria; Behavior; Bypass; Cell Wall; Collection; Development; Escherichia coli; Genes; Gram-Negative Bacteria; Immune response; Immunologic Surveillance; Infection; Institutes; Investigation; Klebsiella; Klebsiella pneumonia bacterium; Lead; Microbial Biofilms; Molecular Weight; Mutation; Names; Natural Products; Pathway interactions; Phagocytosis; Play; Polymers; Polysaccharides; Proteins; Regulation; Regulatory Element; Resolution; Role; Salmonella; Signal Pathway; Signal Transduction; Structure; System; United States National Institutes of Health; Variant; Work; capsule; cell behavior; cell motility; high throughput screening; improved; in vivo Model; innovation; insight; novel; null mutation; pathogenic bacteria; screening; small molecule; small molecule inhibitor

This project aims to identify small molecules to investigate the Rcs pathway. Supported by an NIH Intramural DDIR Innovation Award, the team is pursuing screening of more than 50,000 natural products product extracts from the Natural Products Discovery Institute (NPDI) as a reservoir for identifying new antibiotics. This work should provide a much better understanding of the regulation of capsule synthesis in Klebsiella, possible lead compounds for development of novel antibiotics aimed to change bacterial behavior rather than killing the bacteria, and provide structural insight into some of the unique aspects of the capsule regulatory cascade, relevant to a broad group of gram-negative bacteria. During this period, the collaborative team has successfully optimized a 1536-well high-throughput assay for small molecule screening, which was utilized to screen a number of NCGC's small molecule collections, including a natural product extract collection. Several compounds capable of activating the Rcs pathway have been identified, and these hits have been cherrypicked for further investigation using in vivo models.

该项目旨在识别小分子以研究RCS途径。在美国国立卫生研究院壁内DDIR创新奖的支持下，该团队正在对来自天然产品发现研究所(NPDI)的50,000多种天然产品产品提取物进行筛选，作为识别新抗生素的储存库。这项工作应该能更好地了解克雷伯氏菌胶囊合成的调控，这是开发旨在改变细菌行为而不是杀死细菌的新型抗生素的可能先导化合物，并提供对胶囊调控级联反应的一些独特方面的结构性洞察，与广泛的革兰氏阴性细菌群相关。 在此期间，合作团队成功地优化了1536孔高通量小分子筛选方法，并利用该方法筛选了NCGC的一些小分子样品，包括天然产品提取物样品。几种能够激活RCS途径的化合物已经被鉴定出来，这些化合物已经被筛选出来，用于进一步的体内模型研究。