Targeting virulence regulation to disarm <i>Acinetobacter baumannii</i> pathogenesis.

The development of anti-virulence drug therapy against <i>Acinetobacter baumannii</i> 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 <i>A. baumannii</i> clinical strains in multiple murine and <i>G. mellonella</i> 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 <i>A. baumannii</i>. Moreover, the determination of the structure of the OmpR DNA binding domain of <i>A. baumannii</i> and the development of <i>in vitro</i> 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 <i>A. baumannii</i> infections and we believe that the described platform combining <i>in silico</i> methods, <i>in vitro</i> OmpR inhibitory assays and <i>in vivo G. mellonella</i> surrogate infection model will facilitate future drug discovery programs.