ABRICO

Background and aims. Acinetobacter baumannii is a dreaded pathogen with a great capacity to accumulate many antibiotic resistance mechanisms, leading the World Health Organization to classify it as a top priority for the development of new therapeutic strategies. In addition, recent studies have suggested the existence of strains with increased virulence, without fully identifying the underlying mechanisms. The National Reference Centre for Antimicrobial Resistance in Besançon has identified strains of A. baumannii particularly resistant to antibiotics, especially to carbapenems and polymyxins (colistin), and responsible for a French outbreak. Those phylogenetically indistinguishable strains belong to a clone spreading worldwide. In addition, these strains, whose resistance to polymyxins is mediated by the PmrAB two-component system, are able to multiply in vitro in lung epithelial cells.

The aim of this project is to fully characterise this clone and, in particular, to elucidate the role of PmrAB in its overall pathophysiology.

Implementation. The PmrAB regulon will be assessed using transcriptomics to identify the genetic factors involved in the metabolism of these strains. Adhesion, survival and proliferation capacities in different cell types (phagocytic and non-phagocytic) will also be assessed. The effects of intracellular multiplication will also be studied in vivo in both Galleria mellonella and mice. Finally, the response of human myeloid cells to stimulation by purified lipooligosaccharide (LOS) extracted from the strains of interest and by heat-killed bacteria will be assessed, in particular cytokine production. The structure of lipid A and the membrane lipid composition will be determined by targeted and untargeted lipidomic approach.

Relevance to HARMI. This project is a perfect fit for the HARMI approach, which seeks to understand how antibiotic-resistant bacterial strains emerge and spread successfully. This structuring project will lay the foundations for solid and lasting collaboration between Dijon (UMR 1231, DiviOmics platform) and Besançon (UMR 6249), and will bring new skills to researchers in Bourgogne Franche-Comte thanks to the international partnership (Salcedo Lab, University of Wisconsin-Madison).