Endo Thiago Hideo, Santos Mariana Homem de Mello, Scandorieiro Sara, Gonçalves Bruna Carolina, Vespero Eliana Carolina, Perugini Márcia Regina Eches, Pavanelli Wander Rogério, Nakazato Gerson, Kobayashi Renata Katsuko Takayama
Laboratory of Basic and Applied Bacteriology, Department of Microbiology, Center of Biological Sciences, Universidade Estadual de Londrina, Londrina 86057-970, Brazil.
Laboratory of Innovation and Cosmeceutical Technology, Department of Pharmaceutical Sciences, Center of Health Sciences, Hospital Universitário de Londrina, Londrina 86038-350, Brazil.
Antibiotics (Basel). 2025 Jan 8;14(1):51. doi: 10.3390/antibiotics14010051.
Multidrug-resistant bacteria cause over 700,000 deaths annually, a figure projected to reach 10 million by 2050. 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. 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 μg/mL, while the MIC values for paroxetine ranged from 60 to 250 μg/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 ATCC2 25922 and 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',7'-dichlorodihydrofluorescein diacetate. The drugs also inhibited bacterial efflux pumps, increasing ethidium bromide accumulation and enhancing tetracycline activity in resistant strains. 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.
多重耐药菌每年导致超过70万人死亡，预计到2050年这一数字将达到1000万。在这些细菌中，ESKAPEE组因其多种耐药机制而备受关注。鉴于开发新型抗菌药物的成本高昂以及耐药性的迅速出现，药物重新定位提供了一个有前景的替代方案。本研究评估了舍曲林和帕罗西汀的抗菌活性。当针对ESKAPEE组的临床和参考菌株进行测试时，舍曲林的最低抑菌浓度（MIC）值在15至126μg/mL之间，而帕罗西汀的MIC值在60至250μg/mL之间。两种药物均能在2至24小时内有效根除细菌群体，并导致形态学变化，如突起和细胞破碎，电子扫描显微镜显示了这一点。关于它们作为抗菌药物的作用机制，首次检测到膜通透性增加，这表现为染料吸收增强，同时在ATCC2 25922和ATCC 25923的细胞外培养基中总蛋白和双链DNA的含量增加，在用舍曲林和帕罗西汀处理的细菌中也检测到氧化应激，在抗氧化剂存在的情况下观察到效率降低，并且通过它们与6-羧基-2',7'-二氯二氢荧光素二乙酸酯的反应证明了氧反应性物种水平较高。这些药物还抑制细菌外排泵，增加溴化乙锭的积累并增强耐药菌株中四环素的活性。这些发现表明舍曲林和帕罗西汀可作为针对多重耐药菌的替代治疗药物以及外排泵抑制剂（EPI），并且支持基于这些化合物的抗菌剂的进一步开发。
