Vibrio are a potential source of novel colistin-resistance genes in European coastal environments

Colistin is a widespread last resort antibiotic for treatment of multidrug-resistant bacteria. The recent worldwide emergence of colistin resistance (Col-R) conferred by mcr -1 in human pathogens has raised concern, but the putative sources and reservoirs of novel mcr genes in the marine environment remain underexplored. We observed a high prevalence of Col-R, particularly in Vibrio isolated from European coastal waters by using a unique stock of specific-pathogen-free (SPF) oysters as a bioaccumulator. The high sequence diversity found in the mcr/ept A gene family was geographically structured, particularly for three novel eptA gene variants, which were restricted to the Mediterranean (France, Spain) and occurred as a dgk A- ept A operon controlled by the RstA/RstB two component system. By analyzing 29427 Vibrionaceae genome assemblies, we showed that this mechanism of intrinsic resistance is prevalent and specific to the Harveyi clade, which includes strains of Vibrio parahaemolyticus and Vibrio alginolyticus causing infections in humans. The operon conferred colistin-resistance when transferred to sensitive non- Vibrio strains. While mcr -and arn -based Col-R mechanisms were also identified, the widespread presence of ept A gene variants in Vibrio suggests they play a key role in intrinsic resistance to colistin. Beyond these ancient ept A gene copies having evolved with the Vibrio lineage, we also identified mobile ept A paralogues that have been recently transferred between and within Vibrio clades. This highlights Vibrio as a potential source of Col-R mechanisms, emphasizing the need for enhanced surveillance to prevent colistin-resistant infections in coastal areas.