Role of mobile genetic elements in the global dissemination of the carbapenem resistance gene bla.

The mobile resistance gene bla encodes the NDM enzyme which hydrolyses carbapenems, a class of antibiotics used to treat some of the most severe bacterial infections. The bla gene is globally distributed across a variety of Gram-negative bacteria on multiple plasmids, typically located within highly recombining and transposon-rich genomic regions, which leads to the dynamics underlying the global dissemination of bla to remain poorly resolved. Here, we compile a dataset of over 6000 bacterial genomes harbouring the bla gene, including 104 newly generated PacBio hybrid assemblies from clinical and livestock-associated isolates across China. We develop a computational approach to track structural variants surrounding bla, which allows us to identify prevalent genomic contexts, mobile genetic elements, and likely events in the gene's global spread. We estimate that bla emerged on a Tn125 transposon before 1985, but only reached global prevalence around a decade after its first recorded observation in 2005. The Tn125 transposon seems to have played an important role in early plasmid-mediated jumps of bla, but was overtaken in recent years by other elements including IS26-flanked pseudo-composite transposons and Tn3000. We found a strong association between bla-carrying plasmid backbones and the sampling location of isolates. This observation suggests that the global dissemination of the bla gene was primarily driven by successive between-plasmid transposon jumps, with far more restricted subsequent plasmid exchange, possibly due to adaptation of plasmids to their specific bacterial hosts.