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Among these bacteria, the ESKAPEE group is notable for its multiple resistance mechanisms. Given the high costs of developing new antimicrobials and the rapid emergence of resistance, drug repositioning offers a promising alternative. Results: This study evaluates the antibacterial activity of sertraline and paroxetine. When tested against clinical and reference strains from the ESKAPEE group, sertraline exhibited minimum inhibitory concentration (MIC) values between 15 and 126 \u03bcg\/mL, while the MIC values for paroxetine ranged from 60 to 250 \u03bcg\/mL. Both drugs effectively eradicated bacterial populations within 2 to 24 h and caused morphological changes, such as protrusions and cellular fragmentation, as shown by electron scanning microscopy. Regarding their mechanisms of action as antibacterials, for the first time, increased membrane permeability was detected, as evidenced by heightened dye absorption, along with the increased presence of total proteins and dsDNA in the extracellular medium of Escherichia coli ATCC2 25922 and Staphylococcus aureus ATCC 25923, and oxidative stress was also detected in bacteria treated with sertraline and paroxetine, with reduced efficiency observed in the presence of antioxidants and higher levels of oxygen-reactive species evidenced by their reaction with 6-carboxy-2\u2032,7\u2032-dichlorodihydrofluorescein diacetate. The drugs also inhibited bacterial efflux pumps, increasing ethidium bromide accumulation and enhancing tetracycline activity in resistant strains. Conclusions: These findings indicate that sertraline and paroxetine could serve as alternative treatments against multidrug-resistant bacteria, as well as efflux pump inhibitors (EPIs), and they support further development of antimicrobial agents based on these compounds.<\/jats:p>","DOI":"10.3390\/antibiotics14010051","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T07:40:13Z","timestamp":1736322013000},"page":"51","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Selective Serotonin Reuptake Inhibitors: Antimicrobial Activity Against ESKAPEE Bacteria and Mechanisms of Action"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3830-0426","authenticated-orcid":false,"given":"Thiago Hideo","family":"Endo","sequence":"first","affiliation":[{"name":"Laboratory of Basic and Applied Bacteriology, Department of Microbiology, Center of Biological Sciences, Universidade Estadual de Londrina, Londrina 86057-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7145-709X","authenticated-orcid":false,"given":"Mariana Homem de Mello","family":"Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Basic and Applied Bacteriology, Department of Microbiology, Center of Biological Sciences, Universidade Estadual de Londrina, Londrina 86057-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4012-9100","authenticated-orcid":false,"given":"Sara","family":"Scandorieiro","sequence":"additional","affiliation":[{"name":"Laboratory of Innovation and Cosmeceutical Technology, Department of Pharmaceutical Sciences, Center of Health Sciences, Hospital Universit\u00e1rio de Londrina, Londrina 86038-350, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9958-9112","authenticated-orcid":false,"given":"Bruna Carolina","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Laboratory of Basic and Applied Bacteriology, Department of Microbiology, Center of Biological Sciences, Universidade Estadual de Londrina, Londrina 86057-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3345-153X","authenticated-orcid":false,"given":"Eliana Carolina","family":"Vespero","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Analysis Microbiology Sector, Department of Pathology, Clinical and Toxicological Analysis, Center of Health Sciences, Hospital Universit\u00e1rio de Londrina, Londrina 86038-350, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rcia Regina Eches","family":"Perugini","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Analysis Microbiology Sector, Department of Pathology, Clinical and Toxicological Analysis, Center of Health Sciences, Hospital Universit\u00e1rio de Londrina, Londrina 86038-350, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wander Rog\u00e9rio","family":"Pavanelli","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Protozoology, Department of Pathological Sciences, Center of Biological Sciences, Universidade Estadual de Londrina, Londrina 86057-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerson","family":"Nakazato","sequence":"additional","affiliation":[{"name":"Laboratory of Basic and Applied Bacteriology, Department of Microbiology, Center of Biological Sciences, Universidade Estadual de Londrina, Londrina 86057-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7170-2155","authenticated-orcid":false,"given":"Renata Katsuko Takayama","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Laboratory of Basic and Applied Bacteriology, Department of Microbiology, Center of Biological Sciences, Universidade Estadual de Londrina, Londrina 86057-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1080\/10408398.2015.1077192","article-title":"Antimicrobial Resistance: A Global Emerging Threat to Public Health Systems","volume":"57","author":"Ferri","year":"2017","journal-title":"Crit. 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