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

The mobile resistance gene blaNDM encodes the NDM enzyme which hydrolyses 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 on multiple plasmids, typically located within a highly recombining and transposon-rich genomic region. This complexity means the dynamics underlying the dissemination of blaNDM remain poorly resolved. In this work, we compile a dataset of over 6000 bacterial genomes harbouring the blaNDM gene including 104 newly generated PacBio hybrid assemblies from clinical and livestock associated isolates across China. We develop a novel computational approach to track structural variants surrounding blaNDM in bacterial genomes. This allows us to identify the prevalent genomic contexts of blaNDM and reconstruct the key mobile genetic elements and events in its global spread. We estimate that blaNDM emerged on a Tn125 transposon before 1985 but only reached a global prevalence around a decade after its first recorded observation in 2005. We find that the Tn125 transposon played an important role in early plasmid-mediated jumps of blaNDM but was overtaken by other elements in recent years including IS26-flanked pseudo-composite transposons and Tn3000. Lastly, we observe a notable correlation between plasmid backbones bearing blaNDM and the sampling location of isolates. This observation suggests that the dissemination of resistance genes is mainly driven by successive between-plasmid transposon jumps, with plasmid exchange much more restricted due to the adaptation of plasmids to specific bacterial hosts.