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

## TL;DR

This study explores how VIM-1 metallo-β-lactamase contributes to carbapenem resistance in bacteria and finds that resistance depends on interactions with other genetic factors.

## Contribution

The study reveals that VIM-1-mediated carbapenem resistance requires epistatic interactions with ompC mutations in Enterobacterales.

## Key findings

- VIM-1 is plasmid-borne and globally disseminated in Enterobacterales isolates.
- Carbapenem resistance varies significantly among isolates with VIM-1.
- Resistance requires epistatic interactions with ompC mutations to reduce outer membrane permeability.

## Abstract

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 vim-1+ clinical isolates, from the genera Escherichia, Klebsiella and Enterobacter, were obtained from Kingston, Ontario, Canada. Whole-genome sequencing revealed that vim-1 was plasmid-borne in all strains and situated as the first gene in In916 or In110 integrons. Analysis of related plasmids suggested that these vim-1-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 vim-1 into three common Enterobacterales laboratory strains was not sufficient to confer resistance to ertapenem and meropenem. Instead, adaptive laboratory evolution of the vim-1+ laboratory strains revealed that vim-1-mediated carbapenem resistance in these strains was dependent on epistatic interactions with ompC 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.