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

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 Microbiol

journal_title

Molecular microbiology

authors

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 WM

doi

10.1111/mmi.12306

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

676-89

issue

4

eissn

0950-382X

issn

1365-2958

journal_volume

89

pub_type

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