Antibacterial potential of antidepressants against extended-spectrum β-lactamase-producing Escherichia coli

Antimicrobial resistance in Escherichia coli strains producing extended-spectrum beta-lactamases is a growing global health concern, compounded by the shortage of new antibiotics. Drug repositioning offers a promising alternative, and selective serotonin reuptake inhibitors have recently shown unexpected antibacterial properties. This study evaluated the in vitro antibacterial activity of sertraline, paroxetine, and fluoxetine against extended-spectrum beta-lactamase-producing Escherichia coli, their interactions with ciprofloxacin and meropenem, and their mechanisms of action. Antibacterial activity was assessed by the broth microdilution method, and drug interactions were evaluated using the checkerboard assay. Flow cytometry and fluorescence microscopy were employed to investigate reactive oxygen species generation and DNA damage. The tested compounds exhibited in vitro antibacterial activity, with minimum inhibitory concentrations ranging from 64 to 426.7 μg/mL. Combinations with ciprofloxacin or meropenem showed indifferent effects. Mechanistic analyses revealed that the antidepressants increased reactive oxygen species production and induced DNA damage, leading to apoptosis-like bacterial cell death and a significant reduction in viability. These findings demonstrate that sertraline, paroxetine, and fluoxetine have antibacterial activity against extended-spectrum beta-lactamase-producing Escherichia coli and induce cell death via oxidative stress and genomic damage. Although no synergistic interaction was observed with conventional antibiotics, the data support the potential of these compounds as adjuvants in the treatment of infections caused by multidrug-resistant Escherichia coli.