This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nordfelth, R.
Right arrow Articles by Elofsson, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nordfelth, R.
Right arrow Articles by Elofsson, M.

 Previous Article  |  Next Article 

Infection and Immunity, May 2005, p. 3104-3114, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.3104-3114.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Small-Molecule Inhibitors Specifically Targeting Type III Secretion

R. Nordfelth,1,{dagger} A. M. Kauppi,2,{dagger} H. A. Norberg,3 H. Wolf-Watz,1 and M. Elofsson1,2*

Department of Molecular Biology,1 Organic Chemistry, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden,2 Innate Pharmaceuticals AB, Umestans Företagspark, SE-90347 Umeå, Sweden3

Received 8 September 2004/ Returned for modification 18 October 2004/ Accepted 6 January 2005

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 1 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.

* Corresponding author. Mailing address: Organic Chemistry, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden. Phone: 46-90-786 9328. Fax: 46-90-138885. E-mail: mikael.elofsson{at}chem.umu.se.

Editor: J. B. Bliska

{dagger} These authors have contributed equally to this study.

Infection and Immunity, May 2005, p. 3104-3114, Vol. 73, No. 5
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.5.3104-3114.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tree, J. J., Wang, D., McInally, C., Mahajan, A., Layton, A., Houghton, I., Elofsson, M., Stevens, M. P., Gally, D. L., Roe, A. J. (2009). Characterization of the Effects of Salicylidene Acylhydrazide Compounds on Type III Secretion in Escherichia coli O157:H7. Infect. Immun. 77: 4209-4220 [Abstract] [Full Text]  
  • Puiac, S., Negrea, A., Richter-Dahlfors, A., Plant, L., Rhen, M. (2009). Omeprazole Antagonizes Virulence and Inflammation in Salmonella enterica-Infected RAW264.7 Cells. Antimicrob. Agents Chemother. 53: 2402-2409 [Abstract] [Full Text]  
  • Pan, N. J., Brady, M. J., Leong, J. M., Goguen, J. D. (2009). Targeting Type III Secretion in Yersinia pestis. Antimicrob. Agents Chemother. 53: 385-392 [Abstract] [Full Text]  
  • Veenendaal, A. K. J., Sundin, C., Blocker, A. J. (2009). Small-Molecule Type III Secretion System Inhibitors Block Assembly of the Shigella Type III Secreton. J. Bacteriol. 191: 563-570 [Abstract] [Full Text]  
  • Prantner, D., Nagarajan, U. M. (2009). Role for the Chlamydial Type III Secretion Apparatus in Host Cytokine Expression. Infect. Immun. 77: 76-84 [Abstract] [Full Text]  
  • Jorgensen, I., Valdivia, R. H. (2008). Pmp-Like Proteins Pls1 and Pls2 Are Secreted into the Lumen of the Chlamydia trachomatis Inclusion. Infect. Immun. 76: 3940-3950 [Abstract] [Full Text]  
  • Shen, D.-K., Filopon, D., Chaker, H., Boullanger, S., Derouazi, M., Polack, B., Toussaint, B. (2008). High-cell-density regulation of the Pseudomonas aeruginosa type III secretion system: implications for tryptophan catabolites. Microbiology 154: 2195-2208 [Abstract] [Full Text]  
  • Coburn, B., Sekirov, I., Finlay, B. B. (2007). Type III Secretion Systems and Disease. Clin. Microbiol. Rev. 20: 535-549 [Abstract] [Full Text]  
  • Negrea, A., Bjur, E., Ygberg, S. E., Elofsson, M., Wolf-Watz, H., Rhen, M. (2007). Salicylidene Acylhydrazides That Affect Type III Protein Secretion in Salmonella enterica Serovar Typhimurium. Antimicrob. Agents Chemother. 51: 2867-2876 [Abstract] [Full Text]  
  • Prunier, A.-L., Schuch, R., Fernandez, R. E., Mumy, K. L., Kohler, H., McCormick, B. A., Maurelli, A. T. (2007). nadA and nadB of Shigella flexneri 5a are antivirulence loci responsible for the synthesis of quinolinate, a small molecule inhibitor of Shigella pathogenicity. Microbiology 153: 2363-2372 [Abstract] [Full Text]  
  • Slepenkin, A., Enquist, P.-A., Hagglund, U., de la Maza, L. M., Elofsson, M., Peterson, E. M. (2007). Reversal of the Antichlamydial Activity of Putative Type III Secretion Inhibitors by Iron. Infect. Immun. 75: 3478-3489 [Abstract] [Full Text]  
  • Hudson, D. L., Layton, A. N., Field, T. R., Bowen, A. J., Wolf-Watz, H., Elofsson, M., Stevens, M. P., Galyov, E. E. (2007). Inhibition of Type III Secretion in Salmonella enterica Serovar Typhimurium by Small-Molecule Inhibitors. Antimicrob. Agents Chemother. 51: 2631-2635 [Abstract] [Full Text]  
  • Shakhnovich, E. A., Hung, D. T., Pierson, E., Lee, K., Mekalanos, J. J. (2007). Virstatin inhibits dimerization of the transcriptional activator ToxT. Proc. Natl. Acad. Sci. USA 104: 2372-2377 [Abstract] [Full Text]  
  • Anisimov, A. P., Amoako, K. K. (2006). Treatment of plague: promising alternatives to antibiotics.. J Med Microbiol 55: 1461-1475 [Abstract] [Full Text]  
  • Hilleringmann, M., Pansegrau, W., Doyle, M., Kaufman, S., MacKichan, M. L., Gianfaldoni, C., Ruggiero, P., Covacci, A. (2006). Inhibitors of Helicobacter pylori ATPase Cag{alpha} block CagA transport and cag virulence.. Microbiology 152: 2919-2930 [Abstract] [Full Text]  
  • Muschiol, S., Bailey, L., Gylfe, A., Sundin, C., Hultenby, K., Bergstrom, S., Elofsson, M., Wolf-Watz, H., Normark, S., Henriques-Normark, B. (2006). A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis. Proc. Natl. Acad. Sci. USA 103: 14566-14571 [Abstract] [Full Text]  
  • Yahr, T. L. (2006). A Critical New Pathway for Toxin Secretion?. NEJM 355: 1171-1172 [Full Text]  
  • Logan, S. M. (2006). Flagellar glycosylation - a new component of the motility repertoire?. Microbiology 152: 1249-1262 [Abstract] [Full Text]  
  • Schoenhofen, I. C., Lunin, V. V., Julien, J.-P., Li, Y., Ajamian, E., Matte, A., Cygler, M., Brisson, J.-R., Aubry, A., Logan, S. M., Bhatia, S., Wakarchuk, W. W., Young, N. M. (2006). Structural and Functional Characterization of PseC, an Aminotransferase Involved in the Biosynthesis of Pseudaminic Acid, an Essential Flagellar Modification in Helicobacter pylori. J. Biol. Chem. 281: 8907-8916 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»