β-lactamase expression induces collateral sensitivity in Escherichia coli

Cristina Herencias (), Laura Álvaro-Llorente, Paula Ramiro-Martínez, Ariadna Fernández-Calvet, Ada Muñoz-Cazalla, Javier DelaFuente, Fabrice E. Graf, Laura Jaraba-Soto, Juan Antonio Castillo-Polo, Rafael Cantón, Álvaro San Millán () and Jerónimo Rodríguez-Beltrán ()
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Cristina Herencias: Hospital Universitario Ramón y Cajal
Laura Álvaro-Llorente: Hospital Universitario Ramón y Cajal
Paula Ramiro-Martínez: Hospital Universitario Ramón y Cajal
Ariadna Fernández-Calvet: Centro Nacional de Biotecnología-CSIC
Ada Muñoz-Cazalla: Hospital Universitario Ramón y Cajal
Javier DelaFuente: Centro Nacional de Biotecnología-CSIC
Fabrice E. Graf: University of Gothenburg
Laura Jaraba-Soto: Hospital Universitario Ramón y Cajal
Juan Antonio Castillo-Polo: Hospital Universitario Ramón y Cajal
Rafael Cantón: Hospital Universitario Ramón y Cajal
Álvaro San Millán: Centro Nacional de Biotecnología-CSIC
Jerónimo Rodríguez-Beltrán: Hospital Universitario Ramón y Cajal

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49122-2

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