DOI: 10.1073/pnas.0606412103. A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of <i>Chlamydia trachomatis</i>

A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

10.1073/pnas.0606412103

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis . Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of C. trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3β to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.

Bibliography

Muschiol, S., Bailey, L., Gylfe, Ã., Sundin, C., Hultenby, K., BergstrÃ¶m, 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. Proceedings of the National Academy of Sciences, 103(39), 14566â14571.

Authors 10

Sandra Muschiol (first)
Leslie Bailey (additional)
Åsa Gylfe (additional)
Charlotta Sundin (additional)
Kjell Hultenby (additional)
Sven Bergström (additional)
Mikael Elofsson (additional)
Hans Wolf-Watz (additional)
Staffan Normark (additional)
Birgitta Henriques-Normark (additional)

References 26 Referenced 163

10.1126/science.1116739
10.1016/S1074-5521(03)00046-2
10.1128/IAI.73.5.3104-3114.2005
J Schachter Chlamydia: Intracellular Biology, Pathogenesis, and Immunity, ed RS Stephens (Am Soc Microbiol, Washington, DC), pp. 139–169 (1999). / Chlamydia: Intracellular Biology, Pathogenesis, and Immunity by Schachter J (1999)
10.1016/j.femsre.2005.03.002
10.1002/j.1460-2075.1996.tb00433.x
10.1242/jcs.02733
10.1046/j.1365-2958.1997.4701834.x
10.1128/MMBR.62.2.379-433.1998
10.1073/pnas.0402829101
10.1016/S1286-4579(02)01546-0
10.1046/j.1365-2958.2001.02355.x
10.1046/j.1462-5822.1999.00012.x
10.1073/pnas.98.3.1160
10.1046/j.1365-2958.2000.02212.x
10.1111/j.1365-2958.2005.04647.x
10.1074/jbc.C100693200
10.1084/jem.193.8.935
10.1046/j.1365-2958.1999.01523.x
10.1128/IAI.73.2.905-911.2005
10.1128/IAI.68.1.360-367.2000
10.1099/00221287-148-8-2497
10.1016/S0966-842X(97)82225-1
10.1128/jb.179.23.7233-7242.1997
WJ Newhall Microbiology of Chlamydia, ed AL Barron (CRC, Boca Raton, FL), pp. 47–70 (1988). / Microbiology of Chlamydia by Newhall WJ (1988)
10.1016/S0092-8674(00)80437-7

Dates

Type	When
Created	18 years, 11 months ago (Sept. 14, 2006, 8:46 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 2:50 p.m.)
Indexed	4 months, 1 week ago (April 10, 2025, 7:29 a.m.)
Issued	18 years, 10 months ago (Sept. 26, 2006)
Published	18 years, 10 months ago (Sept. 26, 2006)
Published Online	18 years, 10 months ago (Sept. 26, 2006)
Published Print	18 years, 10 months ago (Sept. 26, 2006)

Funders 0

None

BibTeX

@article{Muschiol_2006, title={A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis}, volume={103}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0606412103}, DOI={10.1073/pnas.0606412103}, number={39}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Muschiol, Sandra and Bailey, Leslie and Gylfe, Åsa and Sundin, Charlotta and Hultenby, Kjell and Bergström, Sven and Elofsson, Mikael and Wolf-Watz, Hans and Normark, Staffan and Henriques-Normark, Birgitta}, year={2006}, month=sep, pages={14566–14571} }

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