title: Antagonism of a zinc metalloprotease using a unique metal-chelating scaffold: tropolones as inhibitors of P. aeruginosa elastase.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, La Jolla, San Diego, CA 92093, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fullagar
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Garner
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Struss
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Day
authors.forename: David P
authors.initials: DP
authors.lastname: Martin
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cai
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000201:enzymology; D014334:Tropolone / Q000737:chemistry* / Q000378:metabolism; D015032:Zinc / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D002614:Chelating Agents; D014334:Tropolone; D010196:Pancreatic Elastase; D015032:Zinc