title: Structure-activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins.
abstract: Four collections of Gal alpha1-4Gal derivatives were synthesised and evaluated as inhibitors of the PapG class II adhesin of uropathogenic Escherichia coli and of the P(N) and P(O) adhesins of Streptococcus suis strains. Galabiosides carrying aromatic structures at C1, methoxyphenyl O-galabiosides in particular, were identified as potent inhibitors of the PapG adhesin. Phenylurea derivatisation at C3' and methoxymethylation at O2' of galabiose provided inhibitors of the S. suis strains type P(N) adhesin with remarkably high affinities (30 and 50 nM, respectively). In addition, quantitative structure-activity relationship models for E. coli PapG adhesin and S. suis adhesin type P(O) were developed using multivariate data analysis. The inhibitory lead structures constitute an advancement towards high-affinity inhibitors as potential anti-adhesion therapeutic agents targeting bacterial infections.
authors.affiliation: Organic Chemistry, Lund University, Sweden.
authors.forename: Jörgen
authors.initials: J
authors.lastname: Ohlsson
authors.forename: Andreas
authors.initials: A
authors.lastname: Larsson
authors.forename: Sauli
authors.initials: S
authors.lastname: Haataja
authors.forename: Jenny
authors.initials: J
authors.lastname: Alajääski
authors.forename: Peter
authors.initials: P
authors.lastname: Stenlund
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Pinkner
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.forename: Jukka
authors.initials: J
authors.lastname: Finne
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
authors.forename: Ulf J
authors.initials: UJ
authors.lastname: Nilsson
mesh_terms: D018829:Adhesins, Bacterial / Q000737:chemistry* / Q000378:metabolism; D018830:Adhesins, Escherichia coli / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004187:Disaccharides / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry; D036781:Fimbriae Proteins / Q000737:chemistry* / Q000378:metabolism; D005690:Galactose / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D005697:Galactosides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006385:Hemagglutination Inhibition Tests; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D015999:Multivariate Analysis; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D017011:Streptococcus suis / Q000737:chemistry; D020349:Surface Plasmon Resonance
chemical_list: D018829:Adhesins, Bacterial; D018830:Adhesins, Escherichia coli; D001426:Bacterial Proteins; D004187:Disaccharides; D005697:Galactosides; C092426:PapG protein, E coli; C032103:4-O-alpha-D-galactopyranosyl-D-galactose; D036781:Fimbriae Proteins; D005690:Galactose