Abstract
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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Our manuscript provides a unique demonstration of an extensive and data-driven analysis of the mobilisation and spread of blaNDM gene, an important agent of bacterial resistance to first-line antibiotics. The revised manuscript now considers a dataset of well over 6,000 bacterial isolates bearing the blaNDM resistance gene (3x the number previously considered). We use a novel method for grouping regions of homology around the gene of interest which we use to inform on the ancestral genetic background of blaNDM and to identify predominant structural variants. We also systematically assess the importance of specific transposable genetic elements in the spread of blaNDM. Our expanded dataset and analysis support the main conclusions made in our initial submission, but we now also report the first phylogenetic estimate of the date of emergence and mobilization of blaNDM. We estimate that this major group of resistance genes first emerged in the mid-20th century, well predating the initial characterisations of NDM-mediated carbapenem resistance, with a second gene mobilisation event by Tn3000 dating to the late 20th century. We retrace the progress of the global dissemination of blaNDM in detail and estimate that the prevalence of resistance reached a stable plateau attained within 8-10 years following the initial rapid global spread. Our work identifies geo-spatial patterns of blaNDM-carrying plasmids, highlighting the importance of successive between-plasmid transposon jumps in resistance dissemination.
