Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis
Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis
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DOI：
10.1111/mmi.12306
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发表时间：
2013-08-01
影响因子：
3.6
通讯作者：
Huston, Wilhelmina M.
中科院分区：
文献类型：
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作者：
Gloeckl, Sarina;Ong, Vanissa A.;Huston, Wilhelmina M.
衣原体是一种全球性的专性细胞内病原体，由于缺乏传统的分子遗传工具来研究这种生物，衣原体发病机制的细节一直困扰着科学家。在这里，我们报告了一种化学生物学策略，发现了这种生物体的第一个必需蛋白酶。鉴定和应用一种独特的CtHtrA抑制剂（JO146）对衣原体的培养导致完全丧失可存活的初级体形成。在繁殖发育阶段，JO146处理导致衣原体细胞形态丧失，包涵体大小减小，最终从宿主细胞中丢失包涵体。这完全阻止了可存活衣原体初级体的形成。JO146除对人沙眼衣原体有抑制作用外，在体内和体外均能抑制小鼠沙眼衣原体的活力。因此，我们报告了一种化学生物学方法来确定衣原体CtHtrA的重要作用。CtHtrA对衣原体的功能似乎对维持细胞复制期的细胞形态至关重要，这些发现证明了蛋白酶可以作为细胞内病原体抗菌治疗的靶点。
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 Chla-mydia 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.