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

Mislav Acman,Shijun Sun,Yuyao Yin,Qi Wang,Nina Luhmann,Ruobing Wang,Hongbin Chen,Francois Balloux,Lucy Van Dorp,Hui Wang,Liam P Shaw

doi:10.1038/s41467-022-28819-2

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. The blaNDM 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 blaNDM to remain poorly resolved. Here, 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 computational approach to track structural variants surrounding blaNDM, which allows us to identify prevalent genomic contexts, mobile genetic elements, and likely events in the gene’s global spread. We estimate that blaNDM 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 blaNDM, but was overtaken in recent years by other elements including IS26-flanked pseudo-composite transposons and Tn3000. We found a strong association between blaNDM-carrying plasmid backbones and the sampling location of isolates. This observation suggests that the global dissemination of the blaNDM 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.

Highlights

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
These include: published assemblies from NCBI RefSeq[33] (n = 2632), NCBI GenBank[34] (n = 1158) and Enterobase[35] (n = 1379); bacterial genomes assembled using short-read de novo assembly from NCBI’s Sequence Read Archive (SRA) (n = 882); and newly generated bacterial genomes isolated from 79 hospitalized patients across China and 25 livestock farms assembled using hybrid PacBio-Illumina de novo assembly (n = 104) (Supplementary Table 1 and Supplementary Fig. 1)
Genetic reshuffling and mobilization of blaNDM by multiple transposons aided its rapid dissemination via a multitude of plasmid backbones

Summary

Introduction

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. We found a strong association between blaNDM-carrying plasmid backbones and the sampling location of isolates. This observation suggests that the global dissemination of the blaNDM 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. BlaNDM encodes a metallo-β-lactamase capable of hydrolyzing most β-lactam antibiotics These antibiotics are used as a first-line treatment for severe infections and to treat multidrug-resistant Gram-negative bacterial infections. Pittii isolate was collected in 2006 from a Turkish patient with no history of travel outside Turkey[8]

Methods

Results

Conclusion