Center for Infectious Diseases and Travel Medicine, University Hospital, and Department of Medicine, Albert-Ludwigs-University, Freiburg, Germany.
J Antimicrob Chemother. 2011 Sep;66(9):2057-60. doi: 10.1093/jac/dkr258. Epub 2011 Jun 23.
To evaluate the antimicrobial and synergistic (hypothetically due to the inhibition of efflux pumps) effects of selective serotonin reuptake inhibitors (SSRIs) in Escherichia coli strains overproducing various resistance-nodulation-division (RND) efflux pumps.
MICs of various SSRIs and of clinically relevant antibiotics in the presence and absence of sertraline were determined for E. coli strains overproducing the RND efflux pumps AcrAB, AcrEF, MdtEF and MexAB. The effect of sertraline on Nile red efflux was evaluated in a real-time efflux assay. Expression of marA and acrB was monitored using quantitative RT-PCR.
In MIC assays there was limited synergy of sertraline with tetracycline, oxacillin, linezolid and clarithromycin, depending on the individual pump overexpressed and on whether rich or minimal medium was used. Sertraline, as the most potent SSRI with regard to bacterial growth inhibition, led to rapid dose-dependent Nile red efflux inhibition, and was also found to increase the expression of marA and acrB.
A possible explanation for the discrepancy between the MIC and real-time efflux assays was that sertraline is a weak inducer of marA and acrB, thereby reducing its initial antibacterial and sensitizing effects over time. The results indicate that sertraline may be useful as a model efflux pump inhibitor for in vitro short-term experiments in E. coli, but is unlikely to be clinically useful as a co-drug against Gram-negative bacteria.
评估选择性 5-羟色胺再摄取抑制剂（SSRIs）在过度表达各种耐药性结节分裂（RND）外排泵的大肠杆菌菌株中的抗菌和协同作用（假设由于外排泵的抑制作用）。
测定了各种 SSRIs 和临床相关抗生素在存在和不存在舍曲林时对过度表达 RND 外排泵 AcrAB、AcrEF、MdtEF 和 MexAB 的大肠杆菌菌株的 MIC。在实时外排测定中评估了舍曲林对尼罗红外排的影响。使用定量 RT-PCR 监测 marA 和 acrB 的表达。
在 MIC 测定中，舍曲林与四环素、苯唑西林、利奈唑胺和克拉霉素的协同作用有限，这取决于过度表达的特定泵以及使用丰富培养基还是最低培养基。舍曲林作为最有效的 SSRI，对细菌生长抑制作用最强，导致快速剂量依赖性尼罗红外排抑制，并且还发现增加了 marA 和 acrB 的表达。
MIC 和实时外排测定之间存在差异的一个可能解释是，舍曲林是 marA 和 acrB 的弱诱导剂，从而随着时间的推移降低其初始的抗菌和增敏作用。结果表明，舍曲林可能可作为体外短期实验中 RND 外排泵抑制剂在大肠杆菌中有用，但不太可能作为针对革兰氏阴性菌的联合药物在临床上有用。
