Inhibition of the ERK/RSK kinase cascade limits Chlamydia trachomatis infection

Chlamydia trachomatis is the most common bacterial sexually transmitted infection worldwide. Azithromycin is effective in treating Chlamydia infection; however, resistance to this antibiotic is increasing, and it is important that new therapeutic strategies are developed. Here, we demonstrated that inhibitors targeting each kinase in the ERK/RSK cascade significantly decreased the size and number of inclusions, as well as the number of infectious progeny. The suppressive effects of the inhibitors were observed across the Chlamydia serotypes D, E, F, and L1 and across Hela, McCoy, and Vero host cells. When combined with azithromycin, all the inhibitors exerted a synergistic suppressive effect on Chlamydia infection. Knockdown experiments using siRNA demonstrated that ERK1/2 and RSK1 were crucial for Chlamydia infection. Moreover, BVD-523, a first-in-class ERK1/2 inhibitor currently undergoing a phase II clinical trial, suppressed Chlamydia infection both in cell culture and in a mouse model. These observations demonstrated not only that the ERK/RSK pathway plays a critical role in Chlamydia infection, but also that these kinases have potential as targets for host-directed therapy against Chlamydia trachomatis.

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