Structure-activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins.
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.
Ohlsson
Jörgen
J
Organic Chemistry, Lund University, Sweden.
Larsson
Andreas
A
Haataja
Sauli
S
Alajääski
Jenny
J
Stenlund
Peter
P
Pinkner
Jerome S
JS
Hultgren
Scott J
SJ
Finne
Jukka
J
Kihlberg
Jan
J
Nilsson
Ulf J
UJ
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
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