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Inhibitors of type III secretion in Yersinia: design, synthesis and multivariate QSAR of 2-sulfonamino-benzanilides
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Innate Pharmaceuticals AB, Umestan Företagspark, SE-90347 Umeå, Sweden.
Innate Pharmaceuticals AB, Umestan Företagspark, SE-90347 Umeå, Sweden.
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, 6994-7011 p.Article in journal (Other academic) Published
Description
Abstract [en]

Compound 1, 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-(3,4-dichloro-phenyl)-benzamide, was identified as a putative type III secretion inhibitor in Yersinia, and the compound thus has a potential to be used to prevent or treat bacterial infections. A set of seven analogues was synthesized and evaluated in a type III secretion dependent reporter-gene assay with viable bacterial to give basic SAR. A second set of 19 compounds was obtained by statistical molecular design in the building block and product space and subsequent synthesis. Evaluation in the reporter-gene assay showed that the compounds ranged from non-active to compounds more potent than 1. Based on the data multivariate QSAR models were established and the final Hi-PLS model showed good correlation between experimentally determined % inhibition and the calculated % inhibition of the reporter-gene signal.

Place, publisher, year, edition, pages
Elsevier Ltd , 2007. Vol. 15, no 22, 6994-7011 p.
Keyword [en]
Type III secretion, Yersinia, Virulence, Inhibitors, Statistical molecular design: multivariate QSAR
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-5559DOI: 10.1016/j.bmc.2007.07.047OAI: oai:DiVA.org:umu-5559DiVA: diva2:145110
Note
Available online 22 August 2007 Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Chemical attenuation of bacterial virulence: small molecule inhibitors of type III secretion
Open this publication in new window or tab >>Chemical attenuation of bacterial virulence: small molecule inhibitors of type III secretion
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Kemi, 2006. 73 p.
Keyword
antibiotic resistance, virulence, type III secretion, T3SS inhibitors, Yop, SMD, QSAR, screening, Yersinia pseudotuberculosis
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-936 (URN)91-7264-178-9 (ISBN)
Public defence
2006-12-08, KB3B1, KBC-huset, Linneaus vägen 10, Umeå Universitet, 90187 Umeå, 10:00 (English)
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Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2011-12-21Bibliographically approved

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Kauppi, Anna M.Andersson, David C.Sundin, CharlottaLinusson Jonsson, AnnaElofsson, Mikael
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