Hamburger James B, Hoertz Amanda J, Lee Amy, Senturia Rachel J, McCafferty Dewey G, Loll Patrick J
Department of Chemistry, Duke University, Durham, NC 27708, USA.
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13759-64. doi: 10.1073/pnas.0904686106. Epub 2009 Aug 3.
The glycodepsipeptide antibiotic ramoplanin A2 is in late stage clinical development for the treatment of infections from Gram-positive pathogens, especially those that are resistant to first line antibiotics such as vancomycin. Ramoplanin A2 achieves its antibacterial effects by interfering with production of the bacterial cell wall; it indirectly inhibits the transglycosylases responsible for peptidoglycan biosynthesis by sequestering their Lipid II substrate. Lipid II recognition and sequestration occur at the interface between the extracellular environment and the bacterial membrane. Therefore, we determined the structure of ramoplanin A2 in an amphipathic environment, using detergents as membrane mimetics, to provide the most physiologically relevant structural context for mechanistic and pharmacological studies. We report here the X-ray crystal structure of ramoplanin A2 at a resolution of 1.4 A. This structure reveals that ramoplanin A2 forms an intimate and highly amphipathic dimer and illustrates the potential means by which it interacts with bacterial target membranes. The structure also suggests a mechanism by which ramoplanin A2 recognizes its Lipid II ligand.
糖肽类抗生素瑞莫拉宁A2正处于治疗革兰氏阳性病原体感染的临床开发后期，尤其是那些对一线抗生素（如万古霉素）耐药的病原体。瑞莫拉宁A2通过干扰细菌细胞壁的产生来实现其抗菌作用；它通过螯合脂质II底物间接抑制负责肽聚糖生物合成的转糖基酶。脂质II的识别和螯合发生在细胞外环境与细菌膜之间的界面处。因此，我们使用去污剂作为膜模拟物，在两亲环境中确定了瑞莫拉宁A2的结构，为机理和药理学研究提供最具生理相关性的结构背景。我们在此报告分辨率为1.4 Å的瑞莫拉宁A2的X射线晶体结构。该结构表明瑞莫拉宁A2形成紧密且高度两亲的二聚体，并说明了其与细菌靶膜相互作用的潜在方式。该结构还提出了瑞莫拉宁A2识别其脂质II配体的机制。
