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Structure-activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: Nanomolar inhibitors of S. suis adhesin.
Umeå University, Faculty of Science and Technology, Chemistry.
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Article in journal (Refereed) Submitted
URN: urn:nbn:se:umu:diva-4091OAI: diva2:143056
Available from: 2004-09-13 Created: 2004-09-13Bibliographically 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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