Sertraline, an antidepressive drug, has been reported to inhibit general bacterial efflux pumps. In the present study, we report for the first time a synergistic effect of sertraline and tetracycline in a TetA-encoded tetracycline-resistant strain of Escherichia coli. Synergy between sertraline and tetracycline in an E. coli strain with TetA-mediated tetracycline resistance (E. coli APEC_O2) was assessed by the MIC and checkerboard assays. The global transcriptome of E. coli APEC_O2 exposed to ½ MIC concentrations of sertraline and/or tetracycline was analyzed to elucidate the interaction mechanism between sertraline and tetracycline. The fractional inhibitory concentration index for tetracycline and sertraline in E. coli APEC_O2 was 0.5. In addition, in the presence of ½ MIC of sertraline, the sensitivity of E. coli APEC_O2 to tetracycline could be restored according to clinical standards (from 64 to 4 mg l^-1). RNA data suggest changes in respiration that is likely to decrease intracellular pH and thereby the proton-motive force, which provides the energy for the tetracycline efflux pump. Furthermore, sertraline and tetracycline may induce a change from oxidation to fermentation in the E.coli, which further decreases pH, resulting in cell death. This study shows that sertraline interacts with tetracycline in a synergistic and AcrAB-TolC pump-independent manner. The combinational treatment was further shown to induce many changes in the global transcriptome, including altered tetA and tetR expression. The results indicate that sertraline may be used as a helper compound with the aim to reverse tetracycline resistance encoded by tetA.

中文翻译：

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深入了解四环素抗性大肠杆菌菌株中四环素和选择性5-羟色胺再摄取抑制剂舍曲林的协同机制。

据报道，舍曲林是一种抗抑郁药，可抑制一般的细菌外排泵。在本研究中，我们首次报告了舍曲林和四环素在大肠杆菌的TetA编码四环素抗性菌株中的协同作用。通过MIC和棋盘分析法评估了具有TetA介导的四环素抗性的大肠杆菌菌株中舍曲林与四环素之间的协同作用。分析了暴露于½MIC浓度舍曲林和/或四环素的大肠杆菌APEC_O2的总体转录组，以阐明舍曲林与四环素之间的相互作用机理。大肠杆菌APEC_O2中四环素和舍曲林的抑制分数浓度分数为0.5。此外，在舍曲林的MIC为½MIC的情况下，E的敏感性较高。^-1）。RNA数据表明呼吸变化可能会降低细胞内pH，从而降低质子动力，从而为四环素外排泵提供能量。此外，舍曲林和四环素可能在大肠杆菌中引起从氧化到发酵的变化，从而进一步降低pH值，导致细胞死亡。这项研究表明，舍曲林以与AcrAB-TolC泵无关的协同方式与四环素相互作用。进一步显示，联合治疗可诱导整体转录组发生许多变化，包括改变tetA和tetR表达。结果表明舍曲林可用作逆转tetA编码的四环素抗性的辅助化合物。