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

该项目旨在鉴定小分子以研究Rcs途径。 在美国国立卫生研究院校内创新奖的支持下，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备。 这项工作应该提供了一个更好的了解克雷伯氏菌的胶囊合成的调节，可能的领导化合物的开发新的抗生素，旨在改变细菌的行为，而不是杀死细菌，并提供结构洞察到一些独特的方面的胶囊监管级联，相关的一个广泛的革兰氏阴性菌。 在此期间，合作团队成功优化了用于小分子筛选的1536孔高通量测定，该测定用于筛选NCGC的许多小分子集合，包括天然产物提取物集合。 已经鉴定了几种能够激活Rcs通路的化合物，并且已经使用体内模型对这些命中进行了进一步研究。

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.