Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus
Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus
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DOI：
10.1128/aac.47.2.719-726.2003
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发表时间：
2003-02-01
影响因子：
4.9
通讯作者：
Kristiansen, JE
中科院分区：
文献类型：
--
作者：
Kaatz, GW;Moudgal, VV;Kristiansen, JE
外排相关的多药耐药（MDR）是细菌逃避选定抗菌药物作用的重要手段。基因组测序数据表明，金黄色葡萄球菌可能拥有许多染色体编码的MDR外排泵，其中大部分尚未得到表征。抑制这些泵，这可能会恢复抗菌剂的临床相关活性，为他们的底物，可能是一个有效的替代寻找新的抗菌剂，不是底物。选择吩噻嗪和噻吨氟哌噻吨的两个几何立体异构体的抑制作用进行了研究，使用菌株的S。金黄色葡萄球菌具有独特的外排相关MDR表型。这些化合物具有一定的内在抗微生物活性，当与常见的MDR外排泵底物结合时，会产生相加或协同作用。对于鼠伤寒沙门氏aureus SA-1199 B，其过表达诺拉MDR外排泵，以及另外两种S.具有非NorA介导的MDR表型的金黄色葡萄球菌中，所有测试化合物对乙锭外排的50%抑制浓度（IC 50）在其各自MIC的4和15%之间。其他底物的转运对抑制不太敏感;丙氯拉嗪对吖啶黄和派洛宁Y外排的IC 50大于其MIC的60%。发现丙氯拉嗪和反式（E）氟哌噻吨可降低S.金黄色葡萄球菌通过降低跨膜电位。我们的结论是吩噻嗪和噻吨抑制流出的PMF依赖泵的机制是多因素的，因为这些化合物的MIC和不同底物的流出的不平衡的影响，可能涉及与泵本身的相互作用，并在较小程度上，减少跨膜电位。
Efflux-related multidrug resistance (MDR) is a significant means by which bacteria can evade the effects of selected antimicrobial agents. Genome sequencing data suggest that Staphylococcus aureus may possess numerous chromosomally encoded MDR efflux pumps, most of which have not been characterized. Inhibition of these pumps, which may restore clinically relevant activity of antimicrobial agents that are substrates for them, may be an effective alternative to the search for new antimicrobial agents that are not substrates. The inhibitory effects of selected phenothiazines and two geometric stereoisomers of the thioxanthene flupentixol were studied using strains of S. aureus possessing unique efflux-related MDR phenotypes. These compounds had some intrinsic antimicrobial activity and, when combined with common MDR efflux pump substrates, resulted in additive or synergistic interactions. For S. aureus SA-1199B, which overexpresses the NorA MDR efflux pump, and for two additional strains of S. aureus having non-NorA-mediated MDR phenotypes, the 50% inhibitory concentration (IC50) for ethidium efflux for all tested compounds was between 4 and 15% of their respective MICs. Transport of other substrates was less susceptible to inhibition; the prochlorperazine IC50 for acriflavine and pyronin Y efflux by SA-1199B was more than 60% of its MIC. Prochlorperazine and trans(E)flupentixol were found to reduce the proton motive force (IMF) of S. aureus by way of a reduction in the transmembrane potential. We conclude that the mechanism by which phenothiazines and thioxanthenes inhibit efflux by PMF-dependent pumps is multifactorial and, because of the unbalanced effect of these compounds on the MICs and the efflux of different substrates, may involve an interaction with the pump itself and, to a lesser extent, a reduction in the transmembrane potential.