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Small-molecule inhibitors specifically targeting type III secretion
Umeå University, Faculty of Medicine, Molecular Biology.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Molecular Biology.
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2005 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 73, no 5, 3104-3114 p.Article in journal (Refereed) Published
Abstract [en]

The type III secretion (TTS) system is used by several animal and plant pathogens to deliver effector proteins into the cytosol of the eukaryotic target cell as a strategy to evade the defense reactions elicited by the infected organism. The fact that these systems are highly homologous implies that novel antibacterial agents that chemically attenuate the pathogens via a specific interaction with the type III secretion mechanism can be identified. A number of small organic molecules having this potential have recently been identified (A. M. Kauppi, R. Nordfelth, H. Uvell, H. Wolf-Watz, and M. Elofsson, Chem. Biol. 10:241-249, 2003). Using different reporter gene constructs, we showed that compounds that belong to a class of acylated hydrazones of different salicylaldehydes target the TTS system of Yersinia pseudotuberculosis. One of these compounds, compound 1, was studied in detail and was found to specifically block Yop effector secretion under in vitro conditions by targeting the TTS system. In this respect the drug mimics the well-known effect of calcium on Yop secretion. In addition, compound I inhibits Yop effector translocation after infection of HeLa cells without affecting the eukaryotic cells or the bacteria. A HeLa cell model that mimics in vivo conditions showed that compound 1 chemically attenuates the pathogen to the advantage of the eukaryotic cell. Thus, our results show proof of concept, i.e., that small compounds targeting the TTS system can be identified, and they point to the possible use of TTS inhibitors as a novel class of antibacterial agents.

Place, publisher, year, edition, pages
Washington: American Society for Microbiology , 2005. Vol. 73, no 5, 3104-3114 p.
Keyword [en]
low-calcium response, yersinia-pseudotuberculosis, antimicrobial chemotherapy, functional conservation, multidrug-resistance, bacterial virulence, escherichia-coli, plasma-membrane, cell contact, protein
URN: urn:nbn:se:umu:diva-13079DOI: doi:10.1128/IAI.73.5.3104-3114.2005OAI: diva2:152750
Available from: 2007-05-02 Created: 2007-05-02 Last updated: 2011-03-10Bibliographically 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.
antibiotic resistance, virulence, type III secretion, T3SS inhibitors, Yop, SMD, QSAR, screening, Yersinia pseudotuberculosis
National Category
Organic Chemistry
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)
Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2011-12-21Bibliographically approved

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