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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洞察四环素抗性大肠杆菌中四环素与选择性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，我们首次报道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。在舍曲林和四环素之间的协同作用的大肠杆菌与TETA介导的四环素抗性（菌株大肠杆菌APEC_O2）由MIC和棋盘测定法进行评估。的全局转录大肠杆菌APEC_O2暴露于½舍曲林和的MIC浓度/对四环素或四环素进行了分析，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。另外，在存在舍曲林的MIC为1 / 2MIC的情况下，可以根据临床标准（64至4mg l ^-1）恢复大肠杆菌APEC_O2对四环素的敏感性。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，舍曲林和四环素可诱导从氧化发酵在一个变化ë。大肠杆菌  ，这会进一步降低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tet A和tet R表达。结果表明，舍曲林可作为逆转tetA编码的四环素耐药性的辅助化合物。