Emergence and Transmission of Plasmid-Mediated Mobile Colistin Resistance Gene mcr-10 in Humans and Companion Animals

Abstract

Mobile colistin resistance (mcr) genes mediated by plasmids have widely disseminated throughout the world. Recently, 10 mcr genes (mcr-1 to mcr-10) and a large number of variants have been identified in more than 60 countries. However, only a few instances of Enterobacter cloacae complex (ECC) bearing mcr-10 from animal origin have been reported globally. The aim of this study was to fill a knowledge gap in mcr-10-positive ECC of animal origin and analyze the potential transmission trend and different characteristics between human and companion animal isolates. The mcr-10 gene was identified on a self-transmissible plasmid in the human isolate and non-transmissible plasmids in other three animal strains. mcr-10 was adjacent to a XerC-type tyrosine recombinase-gene, and various insertion sequences were located on the downstream of core conservative structure xerC-mcr-10, thus indicating this region might be a candidate for insertions of mobile genetic elements and mcr-10 might be mobilized by IS-mediated mechanisms. Moreover, phylogenetic analysis found that mcr-10-positive isolates were mainly distributed in the clade of Enterobacter roggenkampii, exhibiting significant species specificity. These findings indicated that mcr-10 has emerged among Enterobacter spp. within humans and companion animals, highlighting that the importance of taking effective control measures to monitor the dissemination and evolution of mcr genes. IMPORTANCE Colistin was considered as the last-resort drug against severe clinical infections caused by multidrug-resistant Gram-negative pathogens. Mobile colistin resistance (mcr) genes and its variants carried by plasmids have been reported in diverse niches in recent years, and yet few studies reported carriage of mcr-10 in ECC strains of companion animal origin. How plasmid-borne mcr-10 transmitted in opportunistic pathogens and different characteristics of mcr-10-bearing strains isolated from humans and companion animals are not well understood. In this study, we discovered mcr-10-harboring strains in multidrug-resistant ECC isolates of companion animal origin for the first time and conducted a comprehensive analysis of the genetic environment of mcr-10 from multiple countries around the world, providing the potential basis for formulating control measures to slow down the spread of colistin resistance.

Keywords: Enterobacter cloacae complex; companion animals; genetic analysis; mcr-10.

FIG 1

Genetic environment of mcr-10-positive plasmids. GC skew and GC content are indicated from the inside out. The arrows represent the positions and transcriptional directions of the ORFs. Genes are differentiated by colors.

FIG 2

Structural variants downstream of xerC-mcr-10 of 145 isolates (in GenBank, see Table S4 in the supplemental material) and 4 strains in this study. On the left of the figure are the most prevalent structural variations supplied by the Prokka and Roary pipelines. The gray shading indicates the homologous areas between structural variations. Some structural variations and branches were purposefully shortened, despite the fact that their contigs were of appropriate size or greater. A total of 16 types were divided according the downstream structures of mcr-10 and the number of each structure was demonstrated in the below figure. Of which, type XVIII was identified as uncertain structure due to short contig length. Three structures marked with different colors of pentagrams indicated the genetic environment of 4 strains (green, pEk140_mcr-10; blue, pK666_mcr-10 and pK528_mcr-10; gray, pK475-2_mcr-10). The right-hand side shows the distribution of genus, host, and geographical regions of samples that belong to each common structural variant.

FIG 3

Phylogenetic tree of 54 mcr-10-positive Enterobacter genomes. Phylogenetic maximum-likelihood tree generated using iTOL software of SNP analysis performed using the snp-dists tool (see Table S8 in the supplemental material). The clades of E. roggenkampii, E. asburiae, E. sichuanensis, E. hormaechei and E. cloacae are highlighted in light red, blue, yellow, green and purple, respectively. A total of 4 different origins of isolates (human, animal, environmental, and wastewater) are identified.