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

S Gloeckl; Vanissa A Ong; P Patel; J D A Tyndall; Peter Timms; K W Beagley; John A Allan; C W Armitage; L Turnbull; C B Whitchurch; M Merdanovic; M Ehrmann; J C Powers; J Oleksyszyn; M Verdoes; M Bogyo; W M Huston

doi:10.1111/mmi.12306

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

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

S Gloeckl, Vanissa A Ong, P Patel, J D A Tyndall, Peter Timms, K W Beagley, John A Allan, C W Armitage, L Turnbull, C B Whitchurch, …

Molecular Microbiology, Vol.89(4), pp.676-689

2013

DOI: https://doi.org/10.1111/mmi.12306

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Abstract

pathogenesis

Chlamydia

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.

Details

Title: Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis
Authors: S Gloeckl (Author) - Queensland University of Technology
Vanissa A Ong (Author) - Queensland University of Technology
P Patel (Author) - Queensland University of Technology
J D A Tyndall (Author) - University of Otago, New Zealand
Peter Timms (Author) - Queensland University of Technology
K W Beagley (Author) - Queensland University of Technology
John A Allan (Author) - Wesley Research Institute, Australia
C W Armitage (Author) - Queensland University of Technology
L Turnbull (Author) - University of Technology Sydney
C B Whitchurch (Author) - University of Technology Sydney
M Merdanovic (Author) - Uni Duisburg-Essen, Germany
M Ehrmann (Author) - Uni Duisburg-Essen, Germany
J C Powers (Author) - Georgia Institute of Technology, United States
J Oleksyszyn (Author) - Wrocław University of Technology
M Verdoes (Author) - Stanford University School of Medicine, United States
M Bogyo (Author) - Stanford University School of Medicine, United States
W M Huston (Author) - Queensland University of Technology
Publication details: Molecular Microbiology, Vol.89(4), pp.676-689
Publisher: Wiley-Blackwell Publishing Ltd.
Date published: 2013
DOI: 10.1111/mmi.12306
ISSN: 0950-382X
Copyright note: Copyright © 2013 Wiley-Blackwell Publishing Ltd. This is the accepted version of the following article: 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 , which has been published in final form at http://dx.doi.org/10.1111/mmi.12306
Organisation Unit: University of the Sunshine Coast, Queensland; Centre for Bioinnovation
Language: English
Record Identifier: 99448724802621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Microbiology

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