COMPLEX OF FPPS-PV

FPPS-PV复合体

• 批准号: 8170665
• 负责人: Eric Oldfield
• 金额: $ 0.41万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170665
• 关键词: Anabolism; Carotenoids; Commit; Communities; Complex; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; Development; Funding; Grant; Human; Institution; Methicillin Resistance; Mus; Oranges; Physical condensation; Process; Reactive Oxygen Species; Research; Research Personnel; Resistance; Resources; Source; Squalene Synthetase; Staphylococcus aureus; United States National Institutes of Health; Virulence Factors; Virulent; Work; base; dehydrosqualene; design; hypercholesterolemia; inhibitor/antagonist; isoprenoid; killings; neutrophil; resistant strain; staphyloxanthin

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. We are using x-ray and computational methods to guide the development of molecules that inhibit formation of the orange carotenoid virulence factor, staphyloxanthin, in S. aureus. The first committed step in staphyloxanthin biosynthesis is the condensation of two molecules of the isoprenoid farnesyldiphosphate (FPP) to form dehydrosqualene. In recent preliminary work, we have discovered that phosphonosulfonates (human squalene synthase inhibitors which have been developed to treat hypercholesterolemia) also block staphyloxanthin biosynthesis in S. aureus, at 200 nM levels. The resulting S. aureus (L. aureus=golden) are white, non-infective in mice and are killed by neutrophils, since they have decreased defenses to reactive oxygen species (ROS). In Aim 1, we will develop more potent and selective compounds, using NMR, x-ray and computational methods to guide the design process. If successful, this work would be of importance given the increasing number of virulent, community acquired S. aureus and methicillin resistant strains which are becoming highly resistant to ROS based killing.

该副本是利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，这不一定是调查员的机构。 我们正在使用X射线和计算方法来指导抑制金黄色葡萄球菌中橙色类胡萝卜素毒力因子（葡萄糖糖）的形成的分子的发展。葡萄氧甲撒蛋白己糖生物合成的第一个投入步骤是形成脱氢喹啉的异丙型法尼迪磷酸盐（FPP）的两个分子的凝结。在最近的初步工作中，我们发现磷酸磺酸盐（已开发以治疗高胆固醇血症的人类鳞烯合酶抑制剂）也阻断了金黄色葡萄球菌在200 nm水平下的黄霉素生物合成。产生的金黄色葡萄球菌（L.金黄色葡萄球菌=黄金）是白色的，在小鼠中无感染，被嗜中性粒细胞杀死，因为它们减少了对活性氧（ROS）的防御量。在AIM 1中，我们将使用NMR，X射线和计算方法来开发更有效和选择性的化合物来指导设计过程。如果成功的话，这项工作将是重要的，鉴于社区获得了越来越多的有毒的金黄色葡萄球菌和耐甲氧西林菌株，这些菌株正对基于ROS的杀害具有高度抗性。