β-lactamase expression induces collateral sensitivity in Escherichia coli.

Area of Science:

• Microbiology
• Molecular Biology
• Genetics

Background:

• Antimicrobial resistance (AMR) genes are spreading rapidly, diminishing antibiotic effectiveness, particularly in Enterobacterales.
• Beta-lactamases are a common AMR mechanism in Enterobacterales, often linked to mobile genetic elements, necessitating novel countermeasures.
• Collateral sensitivity (CS) offers a potential strategy to combat AMR by exploiting increased susceptibility to one drug upon resistance to another, but typically arises from chromosomal mutations.

Purpose of the Study:

• To investigate collateral sensitivity (CS) responses induced by the acquisition of mobile antibiotic resistance plasmids.
• To determine if the expression of specific beta-lactamase genes can be therapeutically exploited to counteract mobile AMR.
• To assess the prevalence of beta-lactamase-induced CS across different Enterobacterales strains.

Main Methods:

• Dissected the CS response elicited by a prevalent antibiotic resistance plasmid carrying the blaOXA-48 gene.
• Tested the susceptibility of multiple, phylogenetically distinct E. coli strains expressing various clinically relevant mobile beta-lactamases.
• Combined experimental data with large-scale surveillance data from thousands of antibiotic susceptibility tests.

Main Results:

• Expression of the beta-lactamase gene blaOXA-48 induced collateral sensitivity to colistin and azithromycin.
• Other mobile beta-lactamases also elicited similar CS responses in diverse E. coli strains.
• Beta-lactamase-induced CS was found to be pervasive across Enterobacterales.

Conclusions:

• The physiological consequences of beta-lactamase expression can be harnessed for therapeutic benefit.
• This discovery opens avenues for designing targeted therapies to combat or mitigate the impact of mobile AMR.
• Leveraging beta-lactamase-induced collateral sensitivity offers a promising strategy against the global threat of antimicrobial resistance.