Variations in carbapenem resistance associated with the VIM-1 metallo-β-lactamase across the Enterobacterales

The VIM-1 metallo-β-lactamase enzyme, encoded within class 1 integrons, is found in Gram-negative clinical isolates worldwide and has been linked to outbreaks of bacterial pathogens in nosocomial settings. Six <i>vim-1+</i> clinical isolates, from the genera <i>Escherichia</i>, <i>Klebsiella</i> and <i>Enterobacter</i>, were obtained from Kingston, Ontario, Canada. Whole-genome sequencing revealed that <i>vim-1</i> was plasmid-borne in all strains and situated as the first gene in In916 or In110 integrons. Analysis of related plasmids suggested that these <i>vim-1</i>-containing plasmids are globally disseminated and have spread via horizontal gene transfer and autochthonous vertical spread within Ontario. Interestingly, the MICs of ertapenem and meropenem, two clinically relevant carbapenem antibiotics, against these six isolates varied more than tenfold, suggesting that the effects of VIM-1 are dependent on the genomic content of the host microbe. Introducing <i>vim-1</i> into three common <i>Enterobacterales</i> laboratory strains was not sufficient to confer resistance to ertapenem and meropenem. Instead, adaptive laboratory evolution of the <i>vim-1</i> ⁺ laboratory strains revealed that <i>vim-1</i>-mediated carbapenem resistance in these strains was dependent on epistatic interactions with <i>ompC</i> mutations, likely due to decreased outer membrane permeability to these antibiotics. Together, these results provide additional support for the role of gene epistasis in modulating the antimicrobial resistance phenotypes of acquired resistance genes, as well as previous results suggesting that the presence of a β-lactamase gene is insufficient to confer strong resistance to carbapenems without being paired with reduced outer membrane permeability.