Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis

Gloeckl, S; Ong, VA; Patel, P; Tyndall, JDA; Timms, P; Beagley, KW; Allan, JA; Armitage, CW; Turnbull, L; Whitchurch, CB; Merdanovic, M; Ehrmann, M; Powers, JC; Oleksyszyn, J; Verdoes, M; Bogyo, M; Huston, WM

Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis

Gloeckl, S Ong, VA Patel, P Tyndall, JDA Timms, P Beagley, KW Allan, JA Armitage, CW Turnbull, L

Whitchurch, CB

Merdanovic, M Ehrmann, M Powers, JC Oleksyszyn, J Verdoes, M Bogyo, M Huston, WM

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Publication Type:: Journal Article
Citation:: Molecular Microbiology, 2013, 89 (4), pp. 676 - 689
Issue Date:: 2013-08-01

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Field	Value	Language
dc.contributor.author	Gloeckl, S	en_US
dc.contributor.author	Ong, VA	en_US
dc.contributor.author	Patel, P	en_US
dc.contributor.author	Tyndall, JDA	en_US
dc.contributor.author	Timms, P	en_US
dc.contributor.author	Beagley, KW	en_US
dc.contributor.author	Allan, JA	en_US
dc.contributor.author	Armitage, CW	en_US
dc.contributor.author	Turnbull, L https://orcid.org/0000-0002-9255-9033	en_US
dc.contributor.author	Whitchurch, CB https://orcid.org/0000-0003-2296-3791	en_US
dc.contributor.author	Merdanovic, M	en_US
dc.contributor.author	Ehrmann, M	en_US
dc.contributor.author	Powers, JC	en_US
dc.contributor.author	Oleksyszyn, J	en_US
dc.contributor.author	Verdoes, M	en_US
dc.contributor.author	Bogyo, M	en_US
dc.contributor.author	Huston, WM https://orcid.org/0000-0002-0879-1287	en_US
dc.date.available	2013-06-19	en_US
dc.date.issued	2013-08-01	en_US
dc.identifier.citation	Molecular Microbiology, 2013, 89 (4), pp. 676 - 689	en_US
dc.identifier.issn	0950-382X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/26513
dc.description.abstract	The mechanistic details of the pathogenesis of Chlamydia, an obligate intracellular pathogen of global importance, have eluded scientists due to the scarcity of traditional molecular genetic tools to investigate this organism. Here we report a chemical biology strategy that has uncovered the first essential protease for this organism. Identification and application of a unique CtHtrA inhibitor (JO146) to cultures of Chlamydia resulted in a complete loss of viable elementary body formation. JO146 treatment during the replicative phase of development resulted in a loss of Chlamydia cell morphology, diminishing inclusion size, and ultimate loss of inclusions from the host cells. This completely prevented the formation of viable Chlamydia elementary bodies. In addition to its effect on the human Chlamydia trachomatis strain, JO146 inhibited the viability of the mouse strain, Chlamydia muridarum, both in vitro and in vivo. Thus, we report a chemical biology approach to establish an essential role for ChlamydiaCtHtrA. The function of CtHtrA for Chlamydia appears to be essential for maintenance of cell morphology during replicative the phase and these findings provide proof of concept that proteases can be targeted for antimicrobial therapy for intracellular pathogens. © 2013 John Wiley & Sons Ltd.	en_US
dc.relation.ispartof	Molecular Microbiology	en_US
dc.relation.isbasedon	10.1111/mmi.12306	en_US
dc.subject.classification	Microbiology	en_US
dc.subject.mesh	Cell Line	en_US
dc.subject.mesh	Inclusion Bodies	en_US
dc.subject.mesh	Hepatocytes	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Chlamydia trachomatis	en_US
dc.subject.mesh	Dipeptides	en_US
dc.subject.mesh	Serine Proteinase Inhibitors	en_US
dc.subject.mesh	Anti-Bacterial Agents	en_US
dc.subject.mesh	Microscopy	en_US
dc.subject.mesh	Genes, Essential	en_US
dc.subject.mesh	Microbial Viability	en_US
dc.subject.mesh	Serine Proteases	en_US
dc.subject.mesh	Organophosphonates	en_US
dc.title	Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	89	en_US
utslib.for	0605 Microbiology	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	07 Agricultural and Veterinary Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	open_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	89	en_US

Abstract:

The mechanistic details of the pathogenesis of Chlamydia, an obligate intracellular pathogen of global importance, have eluded scientists due to the scarcity of traditional molecular genetic tools to investigate this organism. Here we report a chemical biology strategy that has uncovered the first essential protease for this organism. Identification and application of a unique CtHtrA inhibitor (JO146) to cultures of Chlamydia resulted in a complete loss of viable elementary body formation. JO146 treatment during the replicative phase of development resulted in a loss of Chlamydia cell morphology, diminishing inclusion size, and ultimate loss of inclusions from the host cells. This completely prevented the formation of viable Chlamydia elementary bodies. In addition to its effect on the human Chlamydia trachomatis strain, JO146 inhibited the viability of the mouse strain, Chlamydia muridarum, both in vitro and in vivo. Thus, we report a chemical biology approach to establish an essential role for ChlamydiaCtHtrA. The function of CtHtrA for Chlamydia appears to be essential for maintenance of cell morphology during replicative the phase and these findings provide proof of concept that proteases can be targeted for antimicrobial therapy for intracellular pathogens. © 2013 John Wiley & Sons Ltd.

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http://hdl.handle.net/10453/26513