title: Design and synthesis of C-2 substituted thiazolo and dihydrothiazolo ring-fused 2-pyridones: pilicides with increased antivirulence activity.
abstract: Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.
authors.affiliation: Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Chorell
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Pinkner
authors.forename: Gilles
authors.initials: G
authors.lastname: Phan
authors.forename: Sofie
authors.initials: S
authors.lastname: Edvinsson
authors.forename: Floris
authors.initials: F
authors.lastname: Buelens
authors.forename: Han
authors.initials: H
authors.lastname: Remaut
authors.forename: Gabriel
authors.initials: G
authors.lastname: Waksman
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.forename: Fredrik
authors.initials: F
authors.lastname: Almqvist
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018441:Biofilms / Q000187:drug effects; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D029968:Escherichia coli Proteins / Q000737:chemistry; D010861:Fimbriae, Bacterial / Q000187:drug effects*; D006386:Hemagglutination Tests; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry; D015394:Molecular Structure; D033903:Periplasmic Proteins / Q000737:chemistry; D021122:Protein Subunits / Q000737:chemistry; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D018832:Molecular Chaperones; C084330:PapD protein, E coli; D033903:Periplasmic Proteins; D021122:Protein Subunits; D011728:Pyridones; D013844:Thiazoles