Carbapenem Resistance Mechanisms in Gram-Negative Enterobacteriaceae

Carbapenems constitute a critical class of β-lactam antibiotics reserved for serious infections caused by Gram-negative bacteria. Resistance within Enterobacteriaceae arises predominantly through production of carbapenemase enzymes that hydrolyse the antibiotic core. Major families include class A serine carbapenemases (KPC), class B metallo-β-lactamases (NDM, VIM, IMP) and class D oxacillinases (OXA-48-like). These enzymes are frequently encoded on mobile genetic elements such as plasmids and transposons that facilitate rapid interspecies dissemination. Additional mechanisms include loss or alteration of outer-membrane porins that reduce drug uptake, overexpression of efflux pumps that expel antibiotic molecules and co-occurrence of extended-spectrum β-lactamases that broaden resistance. Horizontal gene transfer mediated by integrons and insertion sequences further accelerates emergence of multidrug-resistant clones in clinical settings. The global spread of carbapenem-resistant Enterobacteriaceae has profound public health implications, diminishing available therapeutic options and increasing morbidity, mortality and healthcare costs. Advances in whole-genome sequencing and molecular surveillance have elucidated the dynamics of resistance gene movement, informing infection control strategies. Clinically, rapid detection of resistance mechanisms underpins targeted therapy and stewardship, while research into novel β-lactamase inhibitors and alternative agents aims to restore efficacy against these formidable pathogens.

Research from Nature Portfolio

Recent studies have dissected the genomic architecture underpinning endemic carbapenem resistance in hospital settings. One investigation analysed two decades of metallo-β-lactamase (blaIMP-4) evolution across clinical and environmental isolates. It revealed that conserved IncC plasmids seeded multi-species outbreaks and that particular “propagator” strain–plasmid pairings enabled persistence through integron and plasmid rearrangements. This work provides a conceptual framework for understanding how carbapenemase genes achieve endemicity via successive genetic diversifications. Another study compiled over 6 000 genomes harbouring the blaNDM gene and employed novel computational methods to track structural variants around resistance cassettes. It demonstrated that early global spread was driven by Tn125 transposon mobilisations, whereas more recent dissemination is dominated by IS26-flanked transposons and Tn3000. Correlations between plasmid backbones and geographic origin highlighted that transposon-mediated jumps between plasmids, rather than wholesale plasmid exchange, have been the principal drivers of global blaNDM movement.

Carbapenem Resistance Mechanisms in Gram-Negative Enterobacteriaceae publication trend

The graph below shows the total number of articles in carbapenem resistance mechanisms in gram-negative enterobacteriaceae across all publications each year (not limited to Nature Index journals).

Technical terms

Carbapenemase: An enzyme that hydrolyses carbapenem antibiotics, rendering them inactive.

Plasmid: A circular, self-replicating DNA molecule that can carry antibiotic-resistance genes between bacteria.

Transposon: A mobile DNA element that can move within and between genomes, often carrying resistance determinants.

Outer-membrane porin: A protein channel in the bacterial outer membrane that permits uptake of small molecules, including antibiotics.

Efflux pump: A membrane-embedded protein complex that exports toxic substances, such as antibiotics, out of the bacterial cell.

References

1. Genomic dissection of endemic carbapenem resistance reveals metallo-beta-lactamase dissemination through clonal, plasmid and integron transfer. Nature Communications (2023).
2. Role of mobile genetic elements in the global dissemination of the carbapenem resistance gene blaNDM. Nature Communications (2022).
3. National genomic epidemiology investigation revealed the spread of carbapenem-resistant Escherichia coli in healthy populations and the impact on public health. Genome Medicine (2024).
4. Rapid cross-border emergence of NDM-5-producing Escherichia coli in the European Union/European Economic Area, 2012 to June 2022. Eurosurveillance (2023).