title: Discovery of two classes of potent glycomimetic inhibitors of Pseudomonas aeruginosa LecB with distinct binding modes.
abstract: The treatment of infections due to the opportunistic pathogen Pseudomonas aeruginosa is often difficult, as a consequence of bacterial biofilm formation. Such a protective environment shields the bacterium from host defense and antibiotic treatment and secures its survival. One crucial factor for maintenance of the biofilm architecture is the carbohydrate-binding lectin LecB. Here, we report the identification of potent mannose-based LecB inhibitors from a screening of four series of mannosides in a novel competitive binding assay for LecB. Cinnamide and sulfonamide derivatives are inhibitors of bacterial adhesion with up to a 20-fold increase in affinity to LecB compared to the natural ligand methyl mannoside. Because many lectins of the host require terminal saccharides (e.g., fucosides), such capped structures as reported here may offer a beneficial selectivity profile for the pathogenic lectin. Both classes of compounds show distinct binding modes at the protein, offering the advantage of a simultaneous development of two new lead structures as anti-pseudomonadal drugs with an anti-virulence mode of action.
authors.affiliation: Department of Chemistry, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hauck
authors.forename: Ines
authors.initials: I
authors.lastname: Joachim
authors.forename: Benjamin
authors.initials: B
authors.lastname: Frommeyer
authors.forename: Annabelle
authors.initials: A
authors.lastname: Varrot
authors.forename: Bodo
authors.initials: B
authors.lastname: Philipp
authors.forename: Heiko M
authors.initials: HM
authors.lastname: Möller
authors.forename: Anne
authors.initials: A
authors.lastname: Imberty
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Exner
authors.forename: Alexander
authors.initials: A
authors.lastname: Titz
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D032701:Biomimetics / Q000145:classification; D002448:Cell Adhesion; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D037102:Lectins / Q000037:antagonists & inhibitors*; D008024:Ligands; D008358:Mannose / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D011485:Protein Binding; D011550:Pseudomonas aeruginosa
chemical_list: C534600:LecB protein, Pseudomonas aeruginosa; D037102:Lectins; D008024:Ligands; D008358:Mannose