Department of Chemistry and Biochemistry, University of California, La Jolla, San Diego, CA 92093, USA.
Chem Commun (Camb). 2013 Apr 21;49(31):3197-9. doi: 10.1039/c3cc41191e. Epub 2013 Mar 12.
Tropolone emerged from the screening of a chelator fragment library (CFL) as an inhibitor of the Zn(2+)-dependent virulence factor, Pseudomonas aeruginosa elastase (LasB). Based on this initial hit, a series of substituted tropolone-based LasB inhibitors was prepared, and a compound displaying potent activity in vitro and in a bacterial swarming assay was identified. Importantly, this inhibitor was found to be specific for LasB over other metalloenzymes, validating the usage of tropolone as a viable scaffold for identifying first-in-class LasB inhibitors.
Tropolone 是从螯合剂片段文库 (CFL) 的筛选中脱颖而出的,是一种锌 (2+) 依赖性毒力因子 Pseudomonas aeruginosa elastase (LasB) 的抑制剂。基于这一初始命中结果,制备了一系列取代的基于 tropolone 的 LasB 抑制剂,并鉴定出一种在体外和细菌群集测定中均显示出强大活性的化合物。重要的是,该抑制剂被发现对 LasB 具有特异性,而对其他金属酶没有活性,这验证了 tropolone 作为鉴定一流 LasB 抑制剂的可行支架的使用。