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Quantitative studies of the binding of the class II PapG adhesin from Uropathogenic Escherichia coli to oligosaccharides.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2003 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 10, 2255-2261 p.Article in journal (Refereed) Published
Abstract [en]

Binding of the class II PapG adhesin, found at the tip of filamentous pili on Escherichia coli, to the carbohydrate moiety of globoseries glycolipids in the human kidney is a key step in development of pyelonephritis, a severe form of urinary tract infection. An assay based on surface plasmon resonance for quantification of the binding of the class II PapG adhesin to oligosaccharides has been developed. Using this assay dissociation constants ranging from 80 to 540 μM were determined for binding of the PapG adhesin to di-pentasaccharide fragments from the globoseries of glycolipids. A series of galabiose derivatives, modified at the anomeric position, O-2′ or O-3′, was also investigated. The anomeric position appeared to be the most promising for development of improved inhibitors of PapG-mediated adhesion of E. colip-Methoxyphenyl galabioside was found to be most potent (Kd=140 μM), and binds to PapG almost as well as the Forssman pentasaccharide.

Place, publisher, year, edition, pages
Elsevier, 2003. Vol. 11, no 10, 2255-2261 p.
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:umu:diva-4090DOI: 10.1016/S0968-0896(03)00114-7OAI: diva2:143055
Available from: 2004-09-13 Created: 2004-09-13 Last updated: 2012-06-07Bibliographically approved
In thesis
1. Antiadhesive agents targeting uropathogenic Escherichia coli: Multivariate studies of protein-protein and protein-carbohydrate interactions
Open this publication in new window or tab >>Antiadhesive agents targeting uropathogenic Escherichia coli: Multivariate studies of protein-protein and protein-carbohydrate interactions
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Antiadhesiva substanser riktade mot uropatogena Escherichia coli : Multivariata studier av protein-protein och protein-kolhydrat interaktioner
Abstract [en]

This thesis describes studies directed towards development of novel antiadhesive agents, with particular emphasis on compounds that prevent attachment of bacteria to a host-cell. Three different proteins involved in the assembly or function of adhesive pili in uropathogenic Escherichia coli have been targeted either by rational structure based design or statistical molecular methods.

A library of substituted galabiose (Galα1-4Gal) derivatives was screened for binding to the E. coli adhesin PapG in an assay based on surface plasmon resonance, and for inhibition of Streptococcus suis adhesins PN and PO in a hemagglutination assay. The results were used to generate QSAR models which had good predictive powers and provided further insight in the structural requirements needed for high affinity binding.

2-pyridones and amino acid derivatives were modelled into the binding site of chaperones involved in pilus assembly in E. coli and a heuristic method, VALIDATE, was used for affinity prediction. The affinity of the compounds for the chaperones PapD and FimC were assessed in assays based on surface plasmon resonance and relaxation-edited NMR spectroscopy. Their ability to disrupt chaperone/subunit complexes was investigated in vitro through a FPLC assay and their capacity to inhibit pilus formation in vivo was determined via hemagglutination and confirmed with atomic force microscopy.

Statistical molecular design was used to design a diverse peptide library targeting pili subunits, and an ELISA was developed to investigate the ability of the peptides to inhibit chaperone/subunit complexation. The resulting QSAR model provided extensive information regarding binding of the peptides to the subunits. Because the peptides were suggested to bind in an extended β-strand formation, β-strand mimetics consisting of oligomeric enaminones were designed. Finally, new methods to synthesize enaminone building blocks were developed using microwave assisted chemistry.

The projects described have generated compounds that besides their value as leads for developing novel antibacterial agents, also constitute new chemical tools to study the mechanisms underlying bacterial virulence.

Place, publisher, year, edition, pages
Umeå: Kemi, 2004. 92 p.
Organic chemistry, Antibacterial, pili, antiadhesive agents, structure based design, statistical molecular design, 2-pyridone, amino acid derivative, galabiose, enaminone, SPR, ELISA, QSAR, Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
urn:nbn:se:umu:diva-314 (URN)91-7305-731-2 (ISBN)
Public defence
2004-10-01, KB3B1, KBC, Umeå Universitet, Umeå, 13:00 (English)
Available from: 2004-09-13 Created: 2004-09-13 Last updated: 2012-06-15Bibliographically approved

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Larsson, AndreasKihlberg, Jan
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