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Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 15, 4522-4532 p.Article in journal (Refereed) Published
Abstract [en]

Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.

Place, publisher, year, edition, pages
Berlin: Wiley-VCH Verlagsgesellschaft, 2012. Vol. 18, no 15, 4522-4532 p.
Keyword [en]
antivirulence, biological activity, coumarin, fluorescence, structure–activity relationships
National Category
Chemical Sciences
URN: urn:nbn:se:umu:diva-53543DOI: 10.1002/chem.201103936PubMedID: 22431310OAI: diva2:513309
Available from: 2012-04-02 Created: 2012-04-02 Last updated: 2013-04-26Bibliographically approved
In thesis
1. Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
Open this publication in new window or tab >>Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections.

Presented herein is a class of antibacterial ring-fused 2-pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent.

The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring-fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed.   

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. 85 p.
Synthesis, 2-pyridone, 2-thiazoline, cross coupling, pili, curli, antibacterial
National Category
Natural Sciences
Research subject
Organic Chemistry
urn:nbn:se:umu:diva-68709 (URN)978-91-7459-552-9 (ISBN)
Public defence
2013-05-24, KBC-Huset, KB3B1, Umeå universitet, Umeå, 10:00 (English)
Available from: 2013-05-03 Created: 2013-04-23 Last updated: 2013-05-03Bibliographically approved

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Chorell, ErikBengtsson, ChristofferEdvinsson, SofieRosenbaum, ErikJohansson, Lennart B-ÅAlmqvist, Fredrik
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)
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Chemistry - A European Journal
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