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Targeting bacterial Virulence:  Inhibitors of type III secretion in Yersinia
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
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2003 (Engelska)Ingår i: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 10, nr 3, s. 241-249Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Agents that target bacterial virulence without detrimental effect on bacterial growth are useful chemical probes for studies of virulence and potential candidates for drug development. Several gram-negative pathogens employ type III secretion to evade the innate immune response of the host. Screening of a chemical library with a luciferase reporter gene assay in viable Yersinia pseudotuberculosis furnished several compounds that inhibit the reporter gene signal expressed from the yopE promoter and effector protein secretion at concentrations with no or modest effect on bacterial growth. The selectivity patterns observed for inhibition of various reporter gene strains indicate that the compounds target the type III secretion machinery at different levels. Identification of this set of inhibitors illustrates the approach of utilizing cell-based assays to identify compounds that affect complex bacterial virulence systems.

Ort, förlag, år, upplaga, sidor
2003. Vol. 10, nr 3, s. 241-249
Identifikatorer
URN: urn:nbn:se:umu:diva-10053DOI: doi:10.1016/S1074-5521(03)00046-2OAI: oai:DiVA.org:umu-10053DiVA, id: diva2:149724
Tillgänglig från: 2008-06-11 Skapad: 2008-06-11 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Chemical attenuation of bacterial virulence: small molecule inhibitors of type III secretion
Öppna denna publikation i ny flik eller fönster >>Chemical attenuation of bacterial virulence: small molecule inhibitors of type III secretion
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Despite the large arsenal of antibiotics available on the market, treatment of bacterial infections becomes more challenging in view of the fact that microbes develop resistance against existing drugs. There is an obvious need for novel drugs acting on both old and new targets in bacteria. In this thesis we have employed a whole cell bacterial assay for screening and identification of type III secretion system (T3SS) inhibitors in Yersinia pseudotuberculosis. The T3SS is a common virulence mechanism utilized by several clinically relevant Gram-negative bacteria including Salmonella, Shigella, Pseudomonas aeruginosa, Chlamydiae and Escherichia coli. Several components in the T3SS have proved to be conserved and hence data generated with Y. pseudotuberculosis as model might also be valid for other bacterial species.

We have screened a 9,400 commercial compound library for T3S inhibitors in Y. pseudotuberculosis using a yopE reporter gene assay. The initial ~ 30 hits were followed up in a growth inhibition assay resulting in 26 interesting compounds that were examined in more detail. Three of the most interesting compounds, salicylanilides, 2-hydroxybenzylidene-hydrazides and 2-arylsulfonamino-benzanilides, were selected for continued investigations. The inhibitor classes show different profiles regarding the effects on T3SS in Yersinia and their use as research tools and identification of the target proteins using a chemical biology approach will increase our understanding of bacterial virulence.

The 2-hydroxybenzylidene-hydrazides have been extensively studied in vitro and show potential as selective T3S inhibitors in several Gram-negative pathogens besides Y. pseudotuberculosis. The data obtained suggest that this inhibitor class targets a conserved protein in the secretion apparatus. In cell-based ex vivo infection models T3SS was inhibited to the advantage of the infected eukaryotic cells. The salicylanilides and 2-arylsulfonamino-benzanilides have been further investigated by statistical molecular design (SMD) followed by synthesis and biological evaluation in the T3SS linked reporter gene assay. Multivariate QSAR models were established despite the challenges with data obtained from assays using viable bacteria. Our results indicate that this SMD QSAR strategy is powerful in development of virulence inhibitors targeting the T3SS.

Ort, förlag, år, upplaga, sidor
Umeå: Kemi, 2006. s. 73
Nyckelord
antibiotic resistance, virulence, type III secretion, T3SS inhibitors, Yop, SMD, QSAR, screening, Yersinia pseudotuberculosis
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-936 (URN)91-7264-178-9 (ISBN)
Disputation
2006-12-08, KB3B1, KBC-huset, Linneaus vägen 10, Umeå Universitet, 90187 Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-11-17 Skapad: 2006-11-17 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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Nordfelth, RolandUvell, HannaWolf-Watz, HansElofsson, Mikael

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Nordfelth, RolandUvell, HannaWolf-Watz, HansElofsson, Mikael
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Kemiska institutionenInstitutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
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Chemistry and Biology

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