Carbapenem Resistance Mechanisms in Enterobacteriaceae

Enterobacteriaceae have acquired resistance to carbapenems through a combination of enzymatic degradation, reduced permeability and active efflux. The principal mechanism is production of carbapenemases, enzymes that hydrolyse carbapenem antibiotics. These comprise class A serine β-lactamases (for example KPC), class B metallo-β-lactamases (for example NDM, VIM, IMP) and class D oxacillinases (for example OXA-48-type). Additional resistance arises from mutations or loss of outer-membrane porins, which limit drug uptake, often in concert with overexpression of efflux pumps. Carbapenemase genes are frequently located on mobile genetic elements—plasmids, integrons and transposons—facilitating rapid dissemination across species and geographic regions. Co-existence of extended-spectrum β-lactamases or AmpC enzymes further compromises remaining therapeutic options. The global spread of carbapenem-resistant Enterobacteriaceae poses a major clinical challenge, with limited treatment alternatives and high mortality in invasive infections. One-health dynamics, encompassing human, animal and environmental reservoirs, underpin the emergence and persistence of resistance, stressing the need for integrated surveillance, antimicrobial stewardship and novel therapeutics.

Research from Nature Portfolio

Recent studies have elucidated molecular drivers of plasmid-mediated spread of NDM-5 carbapenemase. Investigations into IncX3 plasmids reveal a transcriptional regulator, VirBR, that binds upstream of actX and upregulates Type IV secretion system components. This enhancement promotes conjugation efficiency and pili-mediated adhesion, enabling Escherichia coli harbouring blaNDM-5-IncX3 to colonise animal intestines even in the absence of carbapenem pressure. Furthermore, the conjugation process is potentiated by trace copper and zinc ions, indicating that feed and environmental metal content can influence the dissemination of resistance plasmids across one-health interfaces.

Carbapenem Resistance Mechanisms in Enterobacteriaceae publication trend

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

Technical terms

Carbapenemase: Enzyme capable of hydrolysing carbapenem antibiotics, classified into Ambler classes A, B and D.

Metallo-β-lactamase (MBL): Class B carbapenemase requiring zinc ions for activity (e.g., NDM, VIM).

Oxacillinase (OXA-48): Class D carbapenemase often associated with low-level carbapenem hydrolysis and rapid spread.

IncX3 plasmid: A small conjugative plasmid family frequently carrying blaNDM-5 genes.

Type IV secretion system (T4SS): Multi-protein complex mediating DNA and protein transfer between bacterial cells.

Porin: Outer-membrane protein channel that allows diffusion of small molecules, including antibiotics.

Efflux pump: Membrane transporter that actively exports antibiotics and other compounds out of bacterial cells.

Conjugation: Horizontal gene transfer process in which a donor bacterium transfers DNA to a recipient via direct contact.

References

1. VirBR, a transcription regulator, promotes IncX3 plasmid transmission, and persistence of blaNDM-5 in zoonotic bacteria. Nature Communications (2024).
2. Contaminated dicloxacillin capsules as the source of an NDM-5/OXA-48-producing Enterobacter hormaechei ST79 outbreak, Denmark and Iceland, 2022 and 2023. Eurosurveillance (2023).
3. Carbapenem Resistance: A Review. Medical Sciences (2017).
4. Global Spread of Carbapenemase-producing Enterobacteriaceae - Volume 17, Number 10—October 2011 - Emerging Infectious Diseases journal - CDC. Emerging Infectious Diseases (2011).