Massive analysis of 64,628 bacterial genomes to decipher water reservoir and origin of mobile colistin resistance genes: is there another role for these enzymes?

Since 2015, new worrying colistin resistance mechanism, mediated by mcr-1 gene has been reported worldwide along with eight newly described variants but their source(s) and reservoir(s) remain largely unexplored. Here, we conducted a massive bioinformatic analysis of bacterial genomes to investigate the reservoir and origin of mcr variants. We identified 13'658 MCR-1 homologous sequences in 494 bacterial genera. Moreover, analysis of 64'628 bacterial genomes (60 bacterial genera and 1'047 species) allows identifying a total of 6'651 significant positive hits (coverage >90% and similarity >50%) with the nine MCR variants from 39 bacterial genera and more than 1'050 species. A high number of MCR-1 was identified in Escherichia coli (n = 862). Interestingly, while almost all variants were identified in bacteria from different sources (i.e. human, animal, and environment), the last variant, MCR-9, was exclusively detected in bacteria from human. Although these variants could be identified in bacteria from human and animal sources, we found plenty MCR variants in unsuspected bacteria from environmental origin, especially from water sources. The ubiquitous presence of mcr variants in bacteria from water likely suggests another role in the biosphere of these enzymes as an unknown defense system against natural antimicrobial peptides and/or bacteriophage predation.

Study of mcr-1 Gene-Mediated Colistin Resistance in Enterobacteriaceae Isolated from Humans and Animals in Different Countries.

In this study, we aim to characterize the genetic environment of the plasmid-mediated colistin resistance gene mcr-1 in 25 Escherichia coli and seven Klebsiella pneumoniae strains from different countries and continents. Multilocus sequence typing, conjugation experiments, plasmid typing, and the presence and location of the insertion sequence ISApl1 were investigated. Whole genome sequencing of four E. coli was performed to analyse the genetic environment of the mcr-1 gene. Colistin minimum inhibitory concentration of mcr-1 strains varied from 3 to 32 µg/mL. Six E. coli sequence types were detected: ST 4015, ST 3997, ST 10, ST 93, ST 48, and ST 648. IncHI2, IncI2, and IncP plasmid types were predominant and were unrelated to a specific country of origin. ISApl1 was found in 69% of analysed plasmids that were mainly around the mcr-1 gene. Analysis of four closed mcr-1 plasmids revealed the integration of mcr-1 into hotspots. We found that the spread of mcr-1 gene was due to the diffusion of a composite transposon and not to the diffusion of a specific plasmid or a specific bacterial clone. The ease with which the mcr-1 gene integrates into various regions facilitates its dissemination among bacteria and explains its large diffusion all over the world, both in animals and in humans.