Chemical Genetic Identification of Peptidoglycan Inhibitors Potentiating Carbapenem Activity against Methicillin-Resistant Staphylococcus aureus
Chemical Genetic Identification of Peptidoglycan Inhibitors Potentiating Carbapenem Activity against Methicillin-Resistant Staphylococcus aureus
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DOI：
10.1016/j.chembiol.2009.05.012
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发表时间：
2009-08-28
影响因子：
--
通讯作者：
Roemer, Terry
中科院分区：
文献类型：
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作者：
Huber, Joann;Donald, Robert G. K.;Roemer, Terry
耐甲氧西林金黄色葡萄球菌（MRSA）是一种主要的医院和社区获得性病原体，现有的抗生素很少有效。在这里，我们描述了两种结构相关的合成化合物，增强β-内酰胺对MRSA的活性。遗传研究表明，这些药物靶向SAV 1754，基于以下观察结果：（i）其具有独特的化学超敏反应谱，（ii）过表达或点突变足以产生耐药性，（iii）遗传失活表型模拟了这些药物与β-内酰胺类药物联合使用的增效作用。此外，我们证明这些药物抑制肽聚糖的合成。由于SAV 1754是生长所必需的，并且在结构上与最近报道的大肠杆菌的肽聚糖翻转酶相关，我们推测它在S.金黄色。这些结果表明，SAW 754抑制剂可能具有单独治疗潜力，或与β-内酰胺类药物联合治疗，以恢复MRSA的疗效。
Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial and community-acquired pathogen for which few existing antibiotics are efficacious. Here we describe two structurally related synthetic compounds that potentiate P-lactam activity against MRSA. Genetic studies indicate that these agents target SAV1754 based on the following observations: (i) it has a unique chemical hypersensitivity profile, (ii) overexpression or point mutations are sufficient to confer resistance, and (iii) genetic inactivation phenocopies the potentiating effect of these agents in combination with beta-lactams. Further, we demonstrate these agents inhibit peptidoglycan synthesis. Because SAV1754 is essential for growth and structurally related to the recently reported peptidoglycan flippase of Escherichia coli, we speculate it performs an analogous function in S. aureus. These results suggest that SAW 754 inhibitors might possess therapeutic potential alone, or in combination with beta-lactams to restore MRSA efficacy.