DOI: 10.1128/iai.73.5.3104-3114.2005. Small-Molecule Inhibitors Specifically Targeting Type III Secretion

Small-Molecule Inhibitors Specifically Targeting Type III Secretion

10.1128/iai.73.5.3104-3114.2005

Crossref journal-article

American Society for Microbiology

Infection and Immunity (235)

Abstract

ABSTRACT 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.

Bibliography

Nordfelth, R., Kauppi, A. M., Norberg, H. A., Wolf-Watz, H., & Elofsson, M. (2005). Small-Molecule Inhibitors Specifically Targeting Type III Secretion. Infection and Immunity, 73(5), 3104â3114.

Authors 5

R. Nordfelth (first)
A. M. Kauppi (additional)
H. A. Norberg (additional)
H. Wolf-Watz (additional)
M. Elofsson (additional)

References 52 Referenced 183

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Dates

Type	When
Created	20 years, 4 months ago (April 20, 2005, 9:03 p.m.)
Deposited	3 years, 5 months ago (March 5, 2022, 12:48 a.m.)
Indexed	4 months, 1 week ago (April 19, 2025, 7:47 a.m.)
Issued	20 years, 3 months ago (May 1, 2005)
Published	20 years, 3 months ago (May 1, 2005)
Published Print	20 years, 3 months ago (May 1, 2005)

Funders 0

None

BibTeX

@article{Nordfelth_2005, title={Small-Molecule Inhibitors Specifically Targeting Type III Secretion}, volume={73}, ISSN={1098-5522}, url={http://dx.doi.org/10.1128/iai.73.5.3104-3114.2005}, DOI={10.1128/iai.73.5.3104-3114.2005}, number={5}, journal={Infection and Immunity}, publisher={American Society for Microbiology}, author={Nordfelth, R. and Kauppi, A. M. and Norberg, H. A. and Wolf-Watz, H. and Elofsson, M.}, year={2005}, month=may, pages={3104–3114} }

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