Genomic dissection of endemic carbapenem resistance: metallo-beta-lactamase gene dissemination through clonal, plasmid and integron transfer pathways

Abstract

AbstractInfections caused by metallo-beta-lactamase-producing organisms (MBLs) are a global health threat. Our understanding of transmission dynamics and how MBLs establish endemicity remains limited. We analysed two decades ofblaIMP-4evolution in a hospital using sequence data from 270 clinical and environmental isolates (including 169 completed genomes) and identified extreme gene promiscuity across 7 Gram-negative genera, 68 bacterial strains and 7 distinct plasmid types. An initial multi-species outbreak of conserved IncC plasmids (95 genomes across 37 strains) allowed endemicity to be established through the ability ofblaIMP-4to disseminate in successful strain-genetic setting pairs we termed ‘propagators’, in particularSerratia marcescensandEnterobacter hormaechei. From this reservoir,blaIMP-4persisted through diversification of genetic settings that resulted from transfer ofblaIMP-4plasmids between bacterial hosts and of the integron carryingblaIMP-4between plasmids. Our findings provide a framework for understanding endemicity and spread of MBLs and may have broader applicability to other carbapenemase-producing organisms.