Role of the mobilome in the global dissemination of the carbapenem resistance gene blaNDM

Abstract The mobile resistance gene blaNDM encodes the NDM enzyme capable of hydrolysing carbapenems, a class of antibiotics used to treat some of the most severe bacterial infections. blaNDM is globally distributed across a variety of Gram-negative bacteria and is typically located within a highly recombining transposon-rich genomic region common to multiple plasmids types. As a result of this genomic complexity the dynamics underlying the dissemination of blaNDM remain poorly resolved. In this work, we compiled a dataset of over 2000 bacterial genomes harbouring the blaNDM gene including 112 new PacBio hybrid assemblies from clinical and livestock associated isolates across China and developed a novel computational approach to track structural variants in bacterial genomes. We were able to correlate specific structural variants with plasmid backbones, bacterial host species and sampling locations, and identified multiple transposition events that occurred during the global dissemination of blaNDM. Our results highlight the most prominent transposons responsible for the global spread of blaNDM and suggest that genetic recombination, rather than mutation, was the dominant force driving the evolution of the blaNDM genomic region. By tracking the change in diversity among countries of collection of blaNDM-positive genomes, we estimate that blaNDM reached global prevalence within 8-11 years after its initial mobilization. Lastly, we observe notable correlation between plasmid backbones bearing blaNDM and the sampling location which suggests that the dissemination of resistance is mainly driven by successive between-plasmid transposon jumps with plasmid exchange being largely restricted by the boundaries defined by bacterial host-adaptation of individual plasmids.