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.
journal_name
Mol Microbioljournal_title
Molecular microbiologyauthors
Gloeckl S,Ong VA,Patel P,Tyndall JD,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 WMdoi
10.1111/mmi.12306subject
Has Abstractpub_date
2013-08-01 00:00:00pages
676-89issue
4eissn
0950-382Xissn
1365-2958journal_volume
89pub_type
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