Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to <i><scp>C</scp>hlamydia trachomatis</i>

Abstract

Summary The mechanistic details of the pathogenesis of C hlamydia , 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 ( JO 146) to cultures of C hlamydia resulted in a complete loss of viable elementary body formation. JO 146 treatment during the replicative phase of development resulted in a loss of C hlamydia cell morphology, diminishing inclusion size, and ultimate loss of inclusions from the host cells. This completely prevented the formation of viable C hlamydia elementary bodies. In addition to its effect on the human C hlamydia trachomatis strain, JO 146 inhibited the viability of the mouse strain, C hlamydia muridarum , both in vitro and in vivo . Thus, we report a chemical biology approach to establish an essential role for C hlamydia CtHtrA . The function of CtHtrA for C hlamydia 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.