Targeting virulence regulation to disarm pathogenesis.

The development of anti-virulence drug therapy against infections would provide an alternative to traditional antibacterial therapy that are increasingly failing. Here, we demonstrate that the OmpR transcriptional regulator plays a pivotal role in the pathogenesis of diverse clinical strains in multiple murine and invertebrate infection models. We identified OmpR-regulated genes using RNA sequencing and further validated two genes whose expression can be used as robust biomarker to quantify OmpR inhibition in . Moreover, the determination of the structure of the OmpR DNA binding domain of and the development of protein-DNA binding assays enabled the identification of an OmpR small molecule inhibitor. We conclude that OmpR is a valid and unexplored target to fight infections and we believe that the described platform combining methods, OmpR inhibitory assays and surrogate infection model will facilitate future drug discovery programs.