The global distribution and spread of the mobilized colistin resistance gene mcr-1

Abstract

Colistin represents one of the few available drugs for treating infections caused by carbapenem-resistant Enterobacteriaceae. As such, the recent plasmid-mediated spread of the colistin resistance gene mcr-1 poses a significant public health threat, requiring global monitoring and surveillance. Here, we characterize the global distribution of mcr-1 using a data set of 457 mcr-1-positive sequenced isolates. We find mcr-1 in various plasmid types but identify an immediate background common to all mcr-1 sequences. Our analyses establish that all mcr-1 elements in circulation descend from the same initial mobilization of mcr-1 by an ISApl1 transposon in the mid 2000s (2002-2008; 95% highest posterior density), followed by a marked demographic expansion, which led to its current global distribution. Our results provide the first systematic phylogenetic analysis of the origin and spread of mcr-1, and emphasize the importance of understanding the movement of antibiotic resistance genes across multiple levels of genomic organization.

Fig. 1

Overview of the mcr-1-positive isolates included. a Global map of mcr-1-positive isolates included colored by genus with the number and size of pies providing the sample size per location; b Map of novel Chinese isolates sequenced for this study; c Histogram of sampling dates (years) of the isolates. Maps were created using the R package rworldmap using the public domain Natural Earth data set

Fig. 2

Schematic representation of the evolutionary model for the steps in the spread of the mcr-1 gene. (1) The formation of the original composite transposon, followed by (2) transposition between plasmid backgrounds and (3) stabilization via loss of ISApl1 elements before (4) plasmid-mediated spread

Fig. 3

The genetic element carrying mcr-1 is a composite transposon and is alignable across our global data set. a Length distribution of the alignment across sequences. b Length distribution subset by plasmid type. c The composite transposon, consisting of ISApl1, mcr-1, a PAP2 orf, and ISApl1. The region indicated by the red arrow was used in phylogenetic analyses, after the removal of recombination. d The 186 bp region upstream of mcr-1 showed strong signals of recombination (gray box) that coincided with the promotor regions of mcr-1 (red box), and this diverse region was removed from the subsequent alignment. e Twenty-eight sequences from Vietnam had a 1.7 kb insertion containing a putative transpose, suggesting subsequent rearrangement after initial mobilization

Fig. 4

Phylogeny of the mcr-1 composite transposon indicates a dominant sequence type with subsequent diversification. Midpoint-rooted maximum parsimony phylogeny based on the 3522 bp alignment of 457 sequences (recombinant regions removed). Size of points indicates the number of identical sequences, with a representative sequence for each shown next to each tip

Fig. 5

The distribution of plasmid types shown on the transposon phylogeny. Maximum parsimony tree (homoplastic sites removed, midpoint rooted, as in Fig. 4) based on the composite transposon alignment for 172 sequences containing a plasmid replicon on the same contig i.e. those with an assigned plasmid type (color). IncI2 and IncX4 are the most common plasmid types. An example sequence ID is shown for each unique sequence