da Silva Cecília Rocha, do Amaral Valente Sá Lívia Gurgel, de Farias Cabral Vitória Pessoa, Rodrigues Daniel Sampaio, Moreira Lara Elloyse Almeida, da Costa Érica Rayanne Mota, Ferreira Thais Lima, Silveira Maria Janielly Castelo Branco, do Nascimento Paiva Coutinho Tatiana, Barbosa Letícia Bernardo, Aguiar Igor Gomes, Cavalcanti Bruno Coêlho, Leitão Amanda Cavalcante, de Moraes Manoel Odorico, Nobre Júnior Hélio Vitoriano, de Andrade Neto João Batista
School of Pharmacy, Laboratory of Bioprospection in Antimicrobial Molecules (LABIMAN), Federal University of Ceará, Fortaleza, CE, Brazil.
Center of Drug Research and Development (NPDM), Federal University of Ceará, Fortaleza, CE, Brazil.
Folia Microbiol (Praha). 2025 Sep 15. doi: 10.1007/s12223-025-01339-4.
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.
产超广谱β-内酰胺酶的大肠杆菌菌株中的抗菌药物耐药性是一个日益严重的全球健康问题，新抗生素的短缺使这一问题更加复杂。药物重新定位提供了一种有前景的替代方法，并且选择性5-羟色胺再摄取抑制剂最近显示出意想不到的抗菌特性。本研究评估了舍曲林、帕罗西汀和氟西汀对产超广谱β-内酰胺酶的大肠杆菌的体外抗菌活性、它们与环丙沙星和美罗培南的相互作用以及它们的作用机制。通过肉汤微量稀释法评估抗菌活性，并使用棋盘法评估药物相互作用。采用流式细胞术和荧光显微镜研究活性氧的产生和DNA损伤。所测试的化合物表现出体外抗菌活性，最低抑菌浓度范围为64至426.7μg/mL。与环丙沙星或美罗培南联合使用显示出无明显作用。机制分析表明，这些抗抑郁药增加了活性氧的产生并诱导了DNA损伤，导致类似凋亡的细菌细胞死亡并使活力显著降低。这些发现表明，舍曲林、帕罗西汀和氟西汀对产超广谱β-内酰胺酶的大肠杆菌具有抗菌活性，并通过氧化应激和基因组损伤诱导细胞死亡。虽然未观察到与传统抗生素的协同相互作用，但这些数据支持了这些化合物作为治疗多重耐药大肠杆菌引起的感染的佐剂的潜力。
