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Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2012 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, nr 15, s. 4522-4532Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Berlin: Wiley-VCH Verlagsgesellschaft, 2012. Vol. 18, nr 15, s. 4522-4532
Nyckelord [en]
antivirulence, biological activity, coumarin, fluorescence, structure–activity relationships
Nationell ämneskategori
Kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-53543DOI: 10.1002/chem.201103936PubMedID: 22431310OAI: oai:DiVA.org:umu-53543DiVA, id: diva2:513309
Tillgänglig från: 2012-04-02 Skapad: 2012-04-02 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
Öppna denna publikation i ny flik eller fönster >>Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.   

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2013. s. 85
Nyckelord
Synthesis, 2-pyridone, 2-thiazoline, cross coupling, pili, curli, antibacterial
Nationell ämneskategori
Naturvetenskap
Forskningsämne
organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-68709 (URN)978-91-7459-552-9 (ISBN)
Disputation
2013-05-24, KBC-Huset, KB3B1, Umeå universitet, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-05-03 Skapad: 2013-04-23 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Chorell, ErikBengtsson, ChristofferEdvinsson, SofieJohansson, Lennart B-ÅAlmqvist, Fredrik

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Chorell, ErikBengtsson, ChristofferEdvinsson, SofieJohansson, Lennart B-ÅAlmqvist, Fredrik
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Kemiska institutionenUmeå Centre for Microbial Research (UCMR)
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Chemistry - A European Journal
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