Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis |
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| Authors: | Joel D A Tyndall Peter Timms Kenneth W Beagley John A Allan Charles W Armitage Lynne Turnbull Cynthia B Whitchurch Melisa Merdanovic Michael Ehrmann James C Powers Jozef Oleksyszyn Martijn Verdoes Matthew Bogyo Wilhelmina M Huston |
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| Institution: | 1. School of Pharmacy, University of Otago, , Dunedin, New Zealand;2. Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, , Kelvin Grove, Qld, 4059 Australia;3. The Wesley Research Institute, The Wesley Reproductive Medicine and Gynaecological Surgery Unit, , Brisbane, Qld, Australia;4. Microbial Imaging Facility, The iThree institute, University of Technology Sydney, , Sydney, NSW, 2007 Australia;5. ZMB, Uni Duisburg‐Essen, , Essen, Germany;6. School of Chemistry and Biochemistry, Georgia Institute of Technology, , Atlanta, GA, 30332 USA;7. Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wroc?aw University of Technology, , 50‐370 Wroc?aw, Poland;8. Department of Pathology, Stanford University School of Medicine, , Stanford, CA, 94305‐5324 USA |
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| 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 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 targeted for antimicrobial therapy for intracellular pathogens. |
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