Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens
Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens
复制标题
DOI：
10.1021/jm501628s
复制
发表时间：
2015-04-23
影响因子：
7.3
通讯作者：
Shaw, Lindsey N.
中科院分区：
文献类型：
--
作者：
Fleeman, Renee;LaVoi, Travis M.;Shaw, Lindsey N.
基于混合物的合成组合库极大地提高了药物发现速度，允许通过测试呈指数级减少的样品来评估数百万种化合物的活性。在这项研究中，我们使用支架排序文库筛选了 37 个不同的文库，以确定其对 ESKAPE 病原体的抗菌活性。每个库包含 10000 到 750000 个结构类似物，总共超过 600 万种化合物。由此，我们鉴定了一个具有很强抗菌活性的双环胍库。开发了这些化合物的位置扫描库并用于识别每个变体位置上最有效的官能团。合成的单个化合物在一定浓度下对所有 ESKAPE 生物体具有广泛活性
Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds. From this, we identified a bis-cyclic guanidine library that displayed strong antibacterial activity. A positional scanning library for these compounds was developed and used to identify the most effective functional groups at each variant position. Individual compounds were synthesized that were broadly active against all ESKAPE organisms at concentrations