umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Pilicides regulate pili expression in E. coli without affecting the functional properties of the pilus rod
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Visa övriga samt affilieringar
2007 (Engelska)Ingår i: Molecular BioSystems, ISSN 1742-206X, Vol. 3, s. 214-218Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The infectious ability of uropathogenic Escherichia coli relies on adhesive fibers, termed pili or fimbriae, that are expressed on the bacterial surface. Pili are multi-protein structures that are formed via a highly preserved assembly and secretion system called the chaperone-usher pathway. We have earlier reported that small synthetic compounds, referred to as pilicides, disrupt both type 1 and P pilus biogenesis in E. coli. In this study, we show that the pilicides do not affect the structure, dynamics or function of the pilus rod. This was demonstrated by first suppressing the expression of P pili in E. coli by pilicide treatment and, next, measuring the biophysical properties of the pilus rod. The reduced abundance of pili was assessed with hemagglutination, atomic force microscopy and Western immunoblot analysis. The biodynamic properties of the pili fibers were determined by optical tweezers force measurements on individual pili and were found to be intact. The presented results establish a potential use of pilicides as chemical tools to study important biological processes e.g. adhesion, pilus biogenesis and the role of pili in infections and biofilm formation.

Ort, förlag, år, upplaga, sidor
Cambridge: Royal Society of Chemistry , 2007. Vol. 3, s. 214-218
Identifikatorer
URN: urn:nbn:se:umu:diva-12792DOI: 10.1039/B613441FOAI: oai:DiVA.org:umu-12792DiVA, id: diva2:152463
Tillgänglig från: 2007-10-03 Skapad: 2007-10-03 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Peptidomimetics based on ring-fused 2-pyridones: probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors
Öppna denna publikation i ny flik eller fönster >>Peptidomimetics based on ring-fused 2-pyridones: probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This thesis describes the synthesis and biological evaluation of highly substituted, ring-fused 2-pyridones. The utility of the bicyclic 2-pyridones to gain fundamental insights into the disease processes of bacterial infections and Alzheimer’s disease has been investigated.

The 2-pyridones have mainly been studied as a new class of anti-infective agents termed pilicides. The function of the pilicides has been explored using uropathogenic E. coli (UPEC) as a prototype pathogen and urinary tract infection as a model disease. The pilicides target the infectious ability of UPEC by inhibiting key proteins (chaperones) in the so-called chaperone-usher pathway, thus preventing the assembly of bacterial surface organelles (pili/fimbriae).

Synthetic pathways to aminomethylate the 2-pyridones have been developed in order to increase their aqueous solubility while retaining biological activity. Also, the importance of a carboxylic acid has been demonstrated in studies with various carboxylate derivatives and by bioisosteric replacement. Moreover, synthetic procedures to extend the backbone of the rigid, dipeptide-mimicking 2-pyridones have been established. This rendered peptidomimetic building blocks and structures that alongside their potential use as pilicides are of more general interest in peptidomimetic-related research.

The potential pilicides have been screened for chaperone affinity using relaxation-edited 1H-NMR spectroscopy. In addition, their ability to inhibit pilus biogenesis in E. coli has been demonstrated by assays of hemagglutination, biofilm formation and attachment to bladder cells, as well as with electron and atomic force microscopy. Moreover, it has been confirmed that pilicides regulate the expression of pili without affecting the biofunctional properties of the pilus rod. This was verified by measurements of individual P pili, on living bacteria, using force measuring optical tweezers. The pilicide binding site was investigated using NMR spectroscopy and X-ray crystallography of a pilicide-chaperone complex. Based on the results obtained, a mechanism whereby the pilicides may inhibit pilus assembly was proposed, which was subsequently experimentally supported by surface plasmon resonance assays and genetic analysis.

Finally, based on the generic 2-pyridone scaffold, a new collection of substituted compounds has been synthesized and validated as inhibitors of Amyloid β (Aβ)-peptide aggregation, which has been suggested to be involved in Alzheimer’s disease.

Ort, förlag, år, upplaga, sidor
Umeå: Kemi, 2006. s. 101
Nyckelord
2-pyridone, peptidomimetic, antibacterial, pili, Escherichia coli, virulence, amyloid, Alzheimer’s.
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-909 (URN)91-7264-157-6 (ISBN)
Disputation
2006-11-24, KB3B1, KBC, Linneaus väg 7, 901 87 Umeå, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-11-02 Skapad: 2006-11-02 Senast uppdaterad: 2011-04-21Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltext

Personposter BETA

Fällman, ErikAxner, OveUhlin, Bernt EricAlmqvist, Fredrik

Sök vidare i DiVA

Av författaren/redaktören
Fällman, ErikAxner, OveUhlin, Bernt EricAlmqvist, Fredrik
Av organisationen
Kemiska institutionenInstitutionen för fysikInstitutionen för molekylärbiologi (Medicinska fakulteten)

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 237 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf