Huber Joann, Donald Robert G K, Lee Sang Ho, Jarantow Lisa Wang, Salvatore Michael J, Meng Xin, Painter Ronald, Onishi Russell H, Occi James, Dorso Karen, Young Katherine, Park Young Whan, Skwish Stephen, Szymonifka Michael J, Waddell Tim S, Miesel Lynn, Phillips John W, Roemer Terry
Department of Infectious Diseases, Merck & Co., Rahway, NJ 07065, USA.
Chem Biol. 2009 Aug 28;16(8):837-48. doi: 10.1016/j.chembiol.2009.05.012.
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 beta-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 SAV1754 inhibitors might possess therapeutic potential alone, or in combination with beta-lactams to restore MRSA efficacy.
耐甲氧西林金黄色葡萄球菌（MRSA）是一种主要的医院内感染和社区获得性病原体，现有的抗生素对其有效的很少。在此，我们描述了两种结构相关的合成化合物，它们可增强β-内酰胺对MRSA的活性。遗传学研究表明，基于以下观察结果，这些药物靶向SAV1754：（i）它具有独特的化学超敏反应谱，（ii）过表达或点突变足以赋予耐药性，以及（iii）基因失活模拟了这些药物与β-内酰胺联合使用时的增强作用。此外，我们证明这些药物抑制肽聚糖合成。由于SAV1754对生长至关重要，且在结构上与最近报道的大肠杆菌肽聚糖翻转酶相关，我们推测它在金黄色葡萄球菌中执行类似的功能。这些结果表明，SAV1754抑制剂单独使用或与β-内酰胺联合使用可能具有恢复MRSA疗效的治疗潜力。
