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

Gloeckl, Sarina, Ong, Vanissa A., Patel, Pooja, Tyndall, Joel D. A., Timms, Peter, Beagley, Kenneth, Allan, John A., Armitage, Charles W., Turnbull, Lynne, Whitchurch, Cynthia B., Merdanovic, Melisa, Ehrmann, Michael, Powers, James C., Oleksyszyn, Jozef, Verdoes, Martijn, Bogyo, Matthew, & Huston, Wilhelmina M. (2013) Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis. Molecular Microbiology, 89(4), pp. 676-689.

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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 C. 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 Chlamydia CtHtrA. 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 targetted for anti-microbial therapy for intracellular pathogens.

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9 citations in Scopus
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11 citations in Web of Science®

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ID Code: 63955
Item Type: Journal Article
Refereed: Yes
Keywords: chlamydia, protease, protease inhibitor, intracellular pathogenesis
DOI: 10.1111/mmi.12306
ISSN: 1365-2958
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > MICROBIOLOGY (060500) > Infectious Agents (060502)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 John Wiley & Sons Ltd
Deposited On: 05 Nov 2013 01:20
Last Modified: 11 Sep 2016 02:58

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