CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE AND SIGNAL TRANSDUCTION

抗生素耐药性和信号转导的晶体学研究

• 批准号: 7602310
• 负责人: FOCCO VAN DEN AKKER
• 金额: $ 0.39万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602310
• 关键词: Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Binding; Clavulanic Acid; Clavulanic Acids; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Cyclic Nucleotides; Development; Funding; Grant; Housing; Human; Hydrogen; Infection; Institution; Ion Channel; Lactamase; Population; Reaction; Research; Research Personnel; Resistance; Resources; Signal Transduction; Solutions; Source; Structure; Sulbactam; Tazobactam; Time; United States National Institutes of Health; Variant; bacterial resistance; beta-Lactamase; design; inhibitor/antagonist; novel; novel strategies; ultra high resolution

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of antibiotic resistance to bacterial infections is a serious human threats and in large part to bacterial ¿¿¿¿¿¿-lactamases. A powerful solution for treating infections is the co-administration of a ¿¿¿¿¿¿-lactamase inhibitor (such as tazobactam, sulbactam, and clavulanic acid) to which unfortunately resistance has emerged. Our proposal is focused on delineating at an atomic level the inhibitor resistance of the novel ¿¿¿¿¿¿-lactamase variants. Our novel approach to trap reaction intermediates is to use in-house Raman crystallography to pre-characterize the inhibitor soaked crystals and determine the type of intermediate as well as the population of this intermediate with respect to time which resulted in three crystal structures of such complexes (Padayatti et al., JBC 2004 & 2005). Current efforts are to focus on inhibitor resistance variants of SHV beta-lactamase, complexes with novel designed inhibitors. High and ultra-high resolution structures are needed to investigate the subtle conformational changes that are expected as well as locate hydrogens that are part of the reaction mechanism. In addition, we have crystallized 4 different cyclic nucleotide binding domains from bacteria that show a significant homology with that of ion channels.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 对细菌感染的抗生素耐药性的发展是对人类的严重威胁，并且在很大程度上对细菌感染构成威胁 ¿ ¿ ¿ ¿ ¿ ¿ -内酰胺酶是治疗感染的有效解决方案。 ¿ ¿ ¿ ¿ ¿ -内酰胺酶抑制剂（例如他唑巴坦、舒巴坦和克拉维酸），不幸的是，已经出现了耐药性，我们的建议重点是在原子水平上描述新型抑制剂的耐药性。 ¿ ¿ ¿ ¿ ¿ -内酰胺酶变体。我们捕获反应的新方法是使用内部拉曼晶体学来预先表征抑制剂浸泡的晶体，并确定中间体的类型以及该中间体相对于时间的数量，从而产生三种晶体结构。此类复合物的研究（Padayatti 等人，JBC 2004 & 2005）。目前的工作重点是 SHV β-内酰胺酶的抑制剂抗性变体、与新型设计的抑制剂的复合物。需要超高分辨率结构来研究预期的微妙构象变化以及定位反应机制的一部分的氢。此外，我们还从细菌中结晶出 4 个不同的环核苷酸结合结构域，这些结构域与该结构具有显着的同源性。离子通道。