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:

• OmpR
• A. baumannii
• virulence
• drug discovery

Acknowledgement

Valentina Lucchini fellowship is supported by the Train2Target project granted from the European Union’s Horizon 2020 framework program for research and innovation (Project #721484). MN acknowledges support by the PSI-FELLOW-II-3i - International Fellowship Program. The project was partially funded by the Swiss Commission for Innovation and Technology (CTI) under the project number 18838.1 PFLS-LS. The work of Vincent Trebosc, Birgit Schellhorn, Olivia Champion, and Christian Kemmer was co-funded by the State Secretariat for Education, Research and Innovation and the European Union within the Impact2 Eurostars Project 12589. We also thank Brad Spellberg and Laurent Poirel for providing A. baumannii strains.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data are fully available without restriction.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21505594.2022.2135273

Additional information

Funding

The work was supported by the Eurostars [12589]; Horizon 2020 Framework Programme [721484]; Swiss Commission for Innovation and Technology (CTI) [18838.1 PFLS-LS].