Cristina Herencias, Laura Álvaro-Llorente, Paula Ramiro-Martínez,...Jerónimo Rodríguez-Beltrán. β-lactamase expression induces collateral sensitivity in Escherichia coli

Nat Commun. 2024 Jun 3

"Our study indicates that when a bacterium acquires resistance to one antibiotic, it does so at the expense of becoming more susceptible to another. Consequently, by identifying the right combination of antibiotics, we can design more effective treatments against resistant or multiresistant bacteria" - Dr. Jerónimo Rodríguez Beltrán-


Major antibiotic groups are losing effectiveness due to the uncontrollable spread of antimicrobial resistance (AMR) genes. Among these, β-lactam resistance genes -encoding β-lactamases- stand as the most common resistance mechanism in Enterobacterales due to their frequent association with mobile genetic elements. In this context, novel approaches that counter mobile AMR are urgently needed. Collateral sensitivity (CS) occurs when the acquisition of resistance to one antibiotic increases susceptibility to another antibiotic and can be exploited to eliminate AMR selectively. However, most CS networks described so far emerge as a consequence of chromosomal mutations and cannot be leveraged to tackle mobile AMR. Here, we dissect the CS response elicited by the acquisition of a prevalent antibiotic resistance plasmid to reveal that the expression of the β-lactamase gene blaOXA-48 induces CS to colistin and azithromycin. We next show that other clinically relevant mobile β-lactamases produce similar CS responses in multiple, phylogenetically unrelated E. coli strains. Finally, by combining experiments with surveillance data comprising thousands of antibiotic susceptibility tests, we show that β-lactamase-induced CS is pervasive within Enterobacterales. These results highlight that the physiological side-effects of β-lactamases can be leveraged therapeutically, paving the way for the rational design of specific therapies to block mobile AMR or at least counteract their effects.

Why do you highlight this publication?

We have shown that when bacteria produce resistance enzymes from the β-lactamase family -the most common resistance mechanism in gram-negative bacteria- they become more susceptible to colistin and azithromycin antibiotics. Therefore, these antibiotics are more effective against resistant bacteria than against susceptible ones. Our study lays the groundwork for creating new combination therapies that can effectively eradicate resistant strains and limit the spread of resistance. Furthermore, by identifying the specific vulnerabilities of resistant bacteria, it is feasible to repurpose antibiotics that have lost their effectiveness and restore their clinical usefulness.

Publication commented by:

Dr. Jerónimo Rodríguez Beltrán

evodynamics lab       

Dr Herencias, Dr Rodríguez-Beltrán and Dr San Millán
Almetrics, June 2024

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