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