Reversal of methicillin resistance in Staphylococcus aureus by thioridazine
Reversal of methicillin resistance in Staphylococcus aureus by thioridazine
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DOI：
10.1093/jac/dkn417
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发表时间：
2008-12-01
影响因子：
5.2
通讯作者：
Kolmos, Hans Jorn
中科院分区：
文献类型：
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作者：
Klitgaard, Janne K.;Skov, Marianne N.;Kolmos, Hans Jorn
硫利达嗪已被证明在体外逆转耐甲氧西林金黄色葡萄球菌（MRSA）中的苯唑西林耐药性。本研究旨在探讨甲硫利达嗪单独或与苯唑西林联合应用是否影响甲氧西林耐药基因mecA的转录和编码蛋白PBP 2a的蛋白水平。mecA的转录分析引物延伸，PBP 2a的蛋白质水平进行了分析，通过蛋白质印迹法在硫利达嗪和苯唑西林的存在下，我们观察到增加的敏感性，甲氧西林的存在下，MRSA对苯唑西林与苯唑西林或硫利达嗪单独生长的细菌相比。在固定量的苯唑西林存在下，mecA的转录随着硫利达嗪浓度的增加而降低。此外，当用苯唑西林和硫利达嗪的组合处理细菌时，PBP 2a的蛋白质水平降低。这两种药物也影响了β-内酰胺酶基因，blaZ的mRNA水平。本研究表明，甲氧西林耐药的甲硫利达嗪在MRSA的逆转可能是由于减少转录的mecA和blaZ，导致PBP 2a的蛋白水平降低。
Thioridazine has been shown to reverse oxacillin resistance in methicillin-resistant Staphylococcus aureus (MRSA) in vitro. The aim of this study was to investigate whether thioridazine alone or in combination with oxacillin affects the transcription of the methicillin resistance gene mecA and the protein level of the encoded protein PBP2a.Viability of MRSA was determined in liquid media in the presence of oxacillin or thioridazine alone or in combination. Transcription of mecA was analysed by primer extension, and the protein level of PBP2a was analysed by western blotting in the presence of thioridazine and oxacillin.We observed an increased susceptibility of MRSA towards oxacillin in the presence of thioridazine compared with bacteria grown with oxacillin or thioridazine alone. Transcription of mecA was reduced with increasing concentrations of thioridazine in the presence of a fixed amount of oxacillin. Furthermore, the protein level of PBP2a was reduced when bacteria were treated with the combination of oxacillin and thioridazine. The two drugs also affected the mRNA level of the beta-lactamase gene, blaZ.The present study indicates that reversal of methicillin resistance by thioridazine in MRSA may be explained by a reduced transcription of mecA and blaZ, resulting in a reduced protein level of PBP2a.