title: Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study.
abstract: Pilicides prevent pili formation and thereby the development of bacterial biofilms in Escherichia coli. We have performed a comprehensive structure activity relationship (SAR) study of the dihydrothiazolo ring-fused 2-pyridone pilicide central fragment by varying all open positions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used to distinguish active from inactive compounds in which polarity proved to be the most important factor for discrimination. A quantitative SAR (QSAR) partial least squares (PLS) model was calculated on the active compounds for prediction of biofilm inhibition activity. In this model, compounds with high inhibitory activity were generally larger, more lipophilic, more flexible and had a lower HOMO. Overall, this resulted in both highly valuable SAR information and potent inhibitors of type 1 pili dependent biofilm formation. The most potent biofilm inhibitor had an EC(50) of 400 nM.
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: Christoffer
authors.initials: C
authors.lastname: Bengtsson
authors.forename: Thomas Sainte-Luce
authors.initials: TS
authors.lastname: Banchelin
authors.forename: Sofie
authors.initials: S
authors.lastname: Edvinsson
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
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*; D018441:Biofilms / Q000187:drug effects; D016002:Discriminant Analysis; D004926:Escherichia coli / Q000187:drug effects* / Q000502:physiology; D010861:Fimbriae, Bacterial / Q000187:drug effects*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011728:Pyridones; C017679:2-hydroxypyridine