Antagonism of a Zinc Metalloprotease Using a Unique Metal-Chelating Scaffold: Tropolones as Inhibitors of P. aeruginosa Elastase

摘要

Tropolone emerged from the screening of a chelator fragment library (CFL) as an inhibitor of the Zn²⁺-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.