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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 对细菌感染的抗生素抗性的发展是一种严重的人类威胁，在很大程度上是细菌»»»» - 乙酰氨酶酶。一种治疗感染的有力解决方案是对不幸的耐药性出现的，对oodactamase抑制剂（例如tazobactam，sulbactam和clavulanic Acid）的共同给药。我们的建议集中于在原子水平上描述新颖的»»»��—乙酰氨酸酶变体的抑制剂抗性。我们对捕获反应中间体的新型方法是使用内部拉曼晶体学来预示抑制剂浸泡的晶体，并确定与时间相对于时间的中间体以及该中间体的种群，从而导致了三种这种复合物的晶体结构（Padayatti等人，JBC 2004＆2005＆2005）。当前的努力是专注于SHVβ-内酰胺酶的抑制剂耐药性变体，即新型设计抑制剂的复合物。需要高和超高的分辨率结构来研究预期的细微构象变化以及定位是反应机理的一部分的氢。此外，我们从细菌中结晶了4个不同的环状核苷酸结合结构域，这些结构域与离子通道的同源物具有显着的同源性。