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
Design and synthesis of fluorescently labeled pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. (Fredrik Almqvist)
Department of Molecular Microbiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Pilicides and curlicides block formation of the E. coli virulence factors pili and curli. 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 using a strategy where key pilicide and curlicide substituents were replaced by fluorophores having similar physicochemical properties. The resulting fluorescent compounds had improved anti-virulence activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing both coumarin and 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide scaffold. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated to the bacteria and seem to discriminate between different bacteria in a population.

Nationell ämneskategori
Infektionsmedicin Organisk kemi Organisk kemi Läkemedelskemi Organisk kemi
Forskningsämne
bioorganisk kemi; infektionssjukdomar; läkemedelskemi; organisk kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-37170OAI: oai:DiVA.org:umu-37170DiVA, id: diva2:358223
Tillgänglig från: 2010-10-21 Skapad: 2010-10-21 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Pilicides and Curlicides: Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence
Öppna denna publikation i ny flik eller fönster >>Pilicides and Curlicides: Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

New strategies are needed to counter the growing problem of bacterial resistance to antibiotics. One such strategy is to design compounds that target bacterial virulence, which could work separately or in concert with conventional bacteriostatic or bactericidal antibiotics. Pilicides are a class of compounds based on a ring-fused 2-pyridone scaffold that target bacterial virulence by blocking the chaperone/usher pathway in E. coli and thereby inhibit the assembly of pili. This thesis describes the design, synthesis, and biological evaluation of compounds based on the pilicide scaffold with the goal of improving the pilicides and expanding their utility. Synthetic pathways have been developed to enable the introduction of substituents at the C-2 position of the pilicide scaffold. Biological evaluation of these compounds demonstrated that some C-2 substituents give rise to significant increases in potency. X-ray crystallography was used to elucidate the structural basis of this improved biological activity. Furthermore, improved methods for the preparation of oxygen-analogues and C-7 substituted derivatives of the pilicide scaffold have been developed. These new methods were used in combination with existing strategies to decorate the pilicide scaffold as part of a multivariate design approach to improve the pilicides and generate structure activity relationships (SARs).

Fluorescent pilicides were prepared using a strategy where selected substituents were replaced with fluorophores having similar physicochemical properties as the original substituents. Many of the synthesized fluorescent compounds displayed potent pilicide activities and can thus be used to study the complex interactions between pilicide and bacteria. For example, when E. coli was treated with fluorescent pilicides, it was found that the compounds were not uniformly distributed throughout the bacterial population, suggesting that the compounds are primarily associated to bacteria with specific properties.

Finally, by studying compounds designed to inhibit the aggregation of Aβ, it was found that some compounds based on the pilicide scaffold inhibit the formation of the functional bacterial amyloid fibers known as curli; these compounds are referred to as 'curlicides'. Some of the curlicides also prevent the formation of pili and thus exhibit dual pilicide-curlicide activity. The potential utility of such 'dual-action' compounds was highlighted by a study of one of the more potent dual pilicide-curlicides in a murine UTI model were the compound was found to significantly attenuate virulence in vivo.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, Kemiska Institutionen, 2010. s. 83
Nyckelord
pilicide, curlicide, anti-virulence, chaperone/usher pathway, antibacterial, pili, curli, Escherichia coli, biofilm inhibitor, 2-pyridone, peptidomimetic
Nationell ämneskategori
Organisk kemi Organisk kemi Läkemedelskemi Organisk kemi Infektionsmedicin
Forskningsämne
bioorganisk kemi; infektionssjukdomar; läkemedelskemi; organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-37161 (URN)978-91-7459-095-1 (ISBN)
Disputation
2010-11-19, KBC-huset, KB3B1, Umeå Universitet, kemiska institutionen, SE-90187, Umeå, 10:33 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-10-29 Skapad: 2010-10-21 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
2. Optical characterization of potential drugs and drug delivery systems
Öppna denna publikation i ny flik eller fönster >>Optical characterization of potential drugs and drug delivery systems
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This Thesis is a characterization study on substances having potency as drugs as well as on a lipid based drug-delivery matrix. The optical properties of newly synthesized molecules with proven pilicide properties have been characterized with several spectroscopic methods. These methods include optical absorption and fluorescence as well as time-resolved fluorescence. Upon covalently linking compounds with high quantum yields of fluorescence to specific parts of the pilicide, the biological impact was found to increase for some of the derivatives. Furthermore, by expanding the aromatic part of the pilicide molecule, a significant increase in the inherent fluorescence was obtained. The S0-S1 absorption band for these molecules was found to originate from an impure electronic transition, vibronically promoted by intensity borrowing from higher electronic states.

Included in this Thesis is the measurement of how deeply some in this class of newly synthesized molecules become situated when placed inside ganglioside GM1 micelles, and how the molecules’ reorientation is affected. By means of radiation-less energy transfer, it was shown that the molecules place themselves close to the hydrophobic-hydrophilic interface inside the GM1 micelles. As a consequence they are exposed to a densely packed environment, which inhibits the free tumbling of the molecule. This restricted tumbling could be measured by means of time-resolved depolarization experiments.

The release of drug-like fluorescent molecules is investigated from a lipid mixture, which upon equilibrium with water forms a mixture of inverted hexagonal and cubic phases. The lipid matrix displayed an extended release over the course of weeks, in vitro, for molecules having a large variation in hydrophobicity.

Ort, förlag, år, upplaga, sidor
Umeå: Kemiska institutionen, Umeå universitet, 2011. s. 35
Nyckelord
Pilicide, Ganglioside GM1 micelles, Drug Delivery, Elecronic Energy Transfer, UV-Vis Absorption, Fluorescence Spectroscopy
Nationell ämneskategori
Fysikalisk kemi
Forskningsämne
fysikalisk kemi
Identifikatorer
urn:nbn:se:umu:diva-40177 (URN)978-91-7459-157-6 (ISBN)
Disputation
2011-03-11, KBC-huset, KB3A9, Umeå Universitet, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-02-18 Skapad: 2011-02-16 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Personposter BETA

Chorell, ErikBengtsson, ChristofferEdvinsson, SofieRosenbaum, ErikJohansson, Lennart B-ÅAlmqvist, Fredrik

Sök vidare i DiVA

Av författaren/redaktören
Chorell, ErikBengtsson, ChristofferEdvinsson, SofieRosenbaum, ErikJohansson, Lennart B-ÅAlmqvist, Fredrik
Av organisationen
Kemiska institutionen
InfektionsmedicinOrganisk kemiOrganisk kemiLäkemedelskemiOrganisk kemi

Sök vidare utanför DiVA

GoogleGoogle Scholar

urn-nbn

Altmetricpoäng

urn-nbn
Totalt: 873 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