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

The mobile resistance gene bla NDM encodes the NDM enzyme which hydrolyses carbapenems, a class of antibiotics used to treat some of the most severe bacterial infections. bla NDM 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 bla NDM remain poorly resolved. In this work, we compile a dataset of over 6000 bacterial genomes harbouring the bla NDM 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 bla NDM in bacterial genomes. This allows us to identify the prevalent genomic contexts of bla NDM and reconstruct the key mobile genetic elements and events in its global spread. We estimate that bla NDM emerged on a Tn 125 transposon before 1985 but only reached a global prevalence around a decade after its first recorded observation in 2005. We find that the Tn 125 transposon played an important role in early plasmid-mediated jumps of bla NDM but was overtaken by other elements in recent years including IS26-flanked pseudo-composite transposons and Tn 3000 . Lastly, we observe a notable correlation between plasmid backbones bearing bla NDM 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. ### Competing Interest Statement The authors have declared no competing interest.