Antagonism of a zinc metalloprotease using a unique metal-chelating scaffold: tropolones as inhibitors of P. aeruginosa elastase

Chem Commun (Camb). 2013 Apr 21;49(31):3197-9. doi: 10.1039/c3cc41191e. Epub 2013 Mar 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Chelating Agents / chemistry*
  • Chelating Agents / metabolism
  • Kinetics
  • Pancreatic Elastase / antagonists & inhibitors*
  • Pancreatic Elastase / metabolism
  • Protein Binding
  • Pseudomonas aeruginosa / enzymology
  • Tropolone / chemistry*
  • Tropolone / metabolism
  • Zinc / chemistry*

Substances

  • Bacterial Proteins
  • Chelating Agents
  • Tropolone
  • Pancreatic Elastase
  • Zinc