Targeting virulence regulation to disarm Acinetobacter baumannii pathogenesis

Abstract

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

Keywords: A. baumannii; OmpR; drug discovery; virulence.

Figure 1.

Role of OmpR in A. baumannii virulence assessed in thigh and septicaemia mouse infection models.

Figure 2.

Role of OmpR in A. baumannii virulence assessed in G. mellonella infection model.

Figure 3.

Identification and confirmation of OmpR-regulated genes.

Figure 4.

Study of OmpR protein-DNA binding using D-ELISA and in silico analysis.

Figure 5.

Structure of the DNA-binding domain of A. baumannii OmpR and computational hotspots analysis.

Figure 6.

OmpR inhibitory activity of VSIS_039.