Discovery of potent inhibitors of PapG adhesins from uropathogenic Escherichia coli through synthesis and evaluation of galabiose derivatives.
The synthesis of two galabioside (Galalpha1-4Gal) collections based on diversification at the O-1 and O-3' atoms is reported. The galabiosides were evaluated as inhibitors of hemagglutination of human erythrocytes by two strains of Escherichia coli that expressed the class I and class II PapG adhesins, respectively. The class I adhesin was found to prefer aromatic substituents both at the O-1 and the O-3' position of the galabiose disaccharide. One galabioside, p-methoxyphenyl [3-O-(m-nitrobenzyl)-alpha-D-galactopyranosyl]-(1-4)-beta-D-galactopyranoside], had an IC(50) value of 4.1 microM, which is the best inhibition of the class I adhesin to date. In the case of the class II adhesin, one inhibitor, 2-[(S)-2-methoxycarbonyl-2-acetamido-ethylthio]ethyl (3-O-3-[2-(methoxycarbonylphenylthio)propyl]-alpha-D-galactopyranosyl)-(1-4)-alpha-D-galactopyranoside, was found to have an IC(50) value of 68 microM, which is the best artificial inhibition of the class II adhesin reported so far with an affinity for the adhesin comparable to that of the natural tetrasaccharide ligand globotetraose.
Ohlsson
Jörgen
J
Bioorganic Chemistry, Lund University, P.O. Box 124, 221 00 Lund (Sweden).
Jass
Jana
J
Uhlin
Bernt Eric
BE
Kihlberg
Jan
J
Nilsson
Ulf J
UJ
D018830:Adhesins, Escherichia coli / Q000145:classification; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors* / Q000145:classification; D005697:Galactosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006384:Hemagglutination / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D013329:Structure-Activity Relationship
D018830:Adhesins, Escherichia coli; D004187:Disaccharides; D005697:Galactosides; C092426:PapG protein, E coli; C032103:4-O-alpha-D-galactopyranosyl-D-galactose; D036781:Fimbriae Proteins