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?

Mariem Ben Khedher,Raymond Ruimy,Toilhata Riziki,Didier Raoult,Sophie Alexandra Baron,Seydina M Diene,Jean-Marc Rolain

doi:10.1038/s41598-020-63167-5

Abstract

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.

Highlights

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
Among the 13’658 retrieved hits, 90,89% (n = 12’410) exhibit aa identity less than 40% with MCR-1 and only 9.11% (n = 1’244) had aa identity >40% with MCR-1. This finding suggests that these phosphoethanolamine transferase (PET) enzymes are not hosted by some bacterial genera but are present in a wide range of bacterial species, demonstrating that these latter are extremely ubiquitous in microorganisms
Colistin resistance has become an increasing concern for human medicine since the emergence and spread of mobile colistin resistance genes[15,17]. The presence of these genes worldwide in all ecosystems including animals, environment and humans raises the question of their sources, origins and roles in a global context of reservoir of antibiotic resistance genes

Summary

Introduction

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. In 2015, a new transferable colistin resistance mechanism has been described, i.e. mcr-1 gene, encoding for a PET15 which nowadays, along with new variants of this gene, has been described worldwide in a wide variety of bacterial species and is believed to pose a major public health concern as it can be widely disseminated among pathogenic bacteria by horizontal transfer via transposons and recombinant plasmids[16,17] These genes have been already reported in almost all common pathogens and in various sources including food, animal, human and environment (water, soil, etc.) samples[13,17]. We conducted a massive bioinformatic analysis of 64’628 downloaded bacterial genomes to investigate, by a neutral approach of identifying sequences by similarity, the presence and the source of mcr gene variants Such approach allows us to speculate that those mobile genes encoding colistin resistance were probably dedicated to this activity because of their ubiquitous presence. This finding demonstrates that mobile colistin resistance genes is probably an example of exaptation of this enzymatic activity from a selfish sequence that challenges the current classification by COGs (cluster of orthologous groups) that postulate an unequivocal link between phylogeny and function

Methods

Results

Conclusion