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Design and evaluation of Pilicides: Potential novel antibacterial agents directed against Uropathogenic Escherichia coli
Organic Chemistry 2 Center for Chemistry and Chemical Engineering Lund Institute of Technology, Lund University P.O. Box 124, SE-221 00 Lund, Sweden.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
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2001 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, ChemBioChem (Online), ISSN '1439-7633', Vol. 2, no 12, 915-918 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Wiley InterScience , 2001. Vol. 2, no 12, 915-918 p.
Keyword [en]
antibiotics, bioorganic chemistry, chaperone proteins, peptidomimetics
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biorganic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-3202OAI: oai:DiVA.org:umu-3202DiVA: diva2:141701
Available from: 2003-11-28 Created: 2003-11-28 Last updated: 2017-12-14Bibliographically 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.
Keyword
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
Identifiers
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)
Opponent
Supervisors
Available from: 2004-09-13 Created: 2004-09-13 Last updated: 2012-06-15Bibliographically approved
2. Synthesis and biological evaluation of Bicyclic β-Lactams and 2-Pyridinones: Pilicides Targeting Pilus Biogenesis in Pathogenic Bacteria
Open this publication in new window or tab >>Synthesis and biological evaluation of Bicyclic β-Lactams and 2-Pyridinones: Pilicides Targeting Pilus Biogenesis in Pathogenic Bacteria
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

New methods have been developed for the synthesis of bicyclic β-lactams and 2-pyridinones by combining acyl Meldrum’s acids and Δ2-thiazolines. The 2-pyridinones were synthesised both in solution using conventional heating or microwave assisted heating as well as by solid supported chemistry.

The compounds (pilicides) were designed to interfere with the assembly of pili in uropathogenic E. coli by inhibiting the periplasmic chaperones. The affinity of the pilicides to the chaperones was investigated with surface plasmon resonance technique (Biacore) and with relaxation-edited 1H NMR spectroscopy experiments. Finally, the pilicides were investigated for their ability to inhibit pili formation in uropathogenic E. coli in a hemagglutination assay, where members of the 2-pyridinone family proved to be able to cause depiliation.

Place, publisher, year, edition, pages
Umeå: Department of Chemistry, Organic Chemistry, Umeå University, 2003. 75 p.
Keyword
Organic chemistry, β-lactam, 2-pyridinone, 2-pyridone, Meldrum’s acid, Δ2-thiazoline, solid-phase synthesis, microwave assisted synthesis, antibacterial, pili, pilicide, Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-165 (URN)91-7305-546-8 (ISBN)
Public defence
2003-12-19, Stora Hörsalen, KBC-huset,, Umeå universitet, Umeå, 13:00 (English)
Opponent
Available from: 2003-11-28 Created: 2003-11-28 Last updated: 2012-05-15Bibliographically approved
3. NMR as a tool in drug research: Structure elucidation of peptidomimetics and pilicide-chaperone complexes
Open this publication in new window or tab >>NMR as a tool in drug research: Structure elucidation of peptidomimetics and pilicide-chaperone complexes
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the last decades NMR spectroscopy has become an invaluable tool both in academic research and in the pharmaceutical industry. This thesis describes applications of NMR spectroscopy in biomedicinal research for structure elucidation of biologically active peptides and peptidomimetics as well as in studies of ligand-protein interactions.

The first part of this thesis describes the theory and methodology of structure calculations of peptides using experimental restraints derived from NMR spectroscopy. This methodology has been applied to novel mimetics of the peptide hormones desmopressin and Leu-enkephalin. The results of these studies highlight the complicating issue of conformational exchange often encountered in structural determination of peptides and how careful analysis of experimental data as well as optimization of experimental conditions can enable structure determinations in such instances. Although the mimetics of both desmopressin and Leu-enkephalin were found to adopt the wanted conformations, they exhibited no or very poor biological activity. These results demonstrate the difficulties in designing peptidomimetics without detailed structural information of the receptors. A stereoselective synthetic route towards XxxΨ[CH2O]Ala pseudodipeptides is also presented. Such pseudodipeptides can be used as isosteric amide bond replacements in peptides in order to increase their resistance towards proteolytic degradation.

The second part of this thesis describes the study of the interaction between compounds that inhibit pilius assembly, pilicides, and periplasmic chaperones from uropathogenic Escherichia coli. Periplasmic chaperones are key components in assembly of pili, i.e. hair-like protein complexes located on the surface of Escherichia coli that cause urinary tract infections. Detailed knowledge about this interaction is important in understanding how pilicides can inhibit pilus assembly by binding to chaperones. Relaxation-edited NMR experiments were used to confirm the affinity of the pilicides for the chaperones and chemical shift mapping was used to study the pilicide-chaperone interaction surface. These studies show that at least two interaction sites are present on the chaperone surface and consequently that two different mechanisms resulting in inhibition of pilus assembly may exist.

Place, publisher, year, edition, pages
Umeå: Kemi, 2004. 66 p.
Keyword
Organic chemistry, NMR, structure calculations, peptidomimetics, desmopressin, Leu-enkephalin, chemical shift mapping, pilicides, chaperones, urinary tract infections., Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-320 (URN)91-7305-724-X (ISBN)
Public defence
2004-10-08, sal KB3B1, KBC-huset, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2004-09-20 Created: 2004-09-20 Last updated: 2010-03-08Bibliographically approved

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10.1002/1439-7633(20011203)2:12<915::AID-CBIC915>3.0.CO;2-M

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