Supplement to Chemical Biology Studies of the Dynamics and Inhibition of Peptidoglycan Biosynthesis

肽聚糖生物合成动力学和抑制的化学生物学研究的补充

• 批准号: 10609340
• 负责人: Michael S VanNieuwenhze
• 金额: $ 13.89万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609340
• 关键词: 20 year old; Address; Aging; Amino Acids; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Area; Award; Bacillus subtilis; Biology; Cell Separation; Cell Wall; Cell division; Cells; Chemicals; Complex; Computer Systems; Coupled; Cyclic Peptides; Cyclodepsipeptides; Data; Depsipeptides; Detection; Development; Equipment; Funding; Funding Opportunities; High Pressure Liquid Chromatography; Intervention; Lipids; Manufacturer Name; Parents; Pathway interactions; Peptidoglycan; Public Health; Recycling; Research; Research Personnel; Resolution; Running; Sampling; Series; System; Time; Universities; Visualization software; improved; instrument; instrumentation; programs

Funding Opportunity Announcement (FOA) Number: PA-20-272 Equipment request for Maximizing Investigators' Research Award R35 136365 (Project Title: Chemical Biology Studies of the Dynamics and Inhibition of Peptidoglycan Biosynthesis) PROJECT SUMMARY This equipment request is being made to significantly enhance our research capabilities in support of our R35 MIRA award. Our funded MIRA application represents the fusion of two complementary research programs that are, broadly described, directed at the urgent public health threat posed by antibiotic resistance. Our MIRA award seeks to capitalize on our discovery of fluorescent D-amino acids (FDAAs) that have provided unprecedented, and heretofore unavailable, tools for the visualization of bacterial cell wall peptidoglycan (PG) dynamics in real time and in live bacterial cells. We have initiated additional studies to elucidate the details of bacterial cell division and cell separation in Bacillus subtilis, and we are seeking to develop new classes of fluorogenic (i.e., “turn- on”) probes that will enable the study of PG synthesis and dynamics in real-time and in live bacterial cells. We will also continue our effort directed at the synthesis and mechanistic study of cyclic depsipeptide antibiotics that inhibit PG biosynthesis. Furthermore, we have recently uncovered data that suggest the cyclic depsipeptides may have a second mechanism of action that involves inhibition of lipid recycling, an essential activity in the PG biosynthesis pathway. The lipid recycling pathway remains to be clearly elucidated and, when coupled with dual-mode activity that may be inherent to these cyclic depsipeptides under study, very promising new avenues for the identification of new antibacterial targets and development of new antibacterial agents are likely to emerge from this research effort. Research in each of these areas requires routine access to HPLC instrumentation with high resolution capabilities with multiple mods of detection. Our current HPLC system is approximately twenty years old and is no longer supported by the manufacturer. In addition, the computer system required to run the instrument has become obsolete and is no longer supported by our university. As a result, this instrument has a significant amount of ‘down time’ that adversely impacts research progress under the parent R35 award. In this application, we are seeking funds for the purchase of an Agilent 1290 Infinity Flex Series HPLC/UHPLC instrument that has the capability for routine purity analysis of amino acids, cyclic peptides, and the like as well as UHPLC capability to enable analysis of more complex samples, such as PG fragments. This instrument will replace our aging and unrepairable system, significantly enhance our analytical capabilities, and have a profoundly positive impact on our activities under the parent R35 award.

资金机会公告（FOA）编号：PA-20-272 设备要求最大化调查人员研究奖R35 136365（项目标题：化学 动力学和抑制肽聚糖生物合成的生物学研究） 项目摘要 正在提出此设备请求，以显着增强我们的研究能力 支持我们的R35 MIRA奖。我们资助的MIRA应用代表了两个的融合 广泛描述的完全研究计划针对URGET公共卫生 抗生素抗性构成的威胁。我们的MIRA奖旨在利用我们的发现 荧光D-氨基酸（FDAA）提供了前所未有的，迄今不可用的 可视化细菌细胞壁Pepperidoglycan（PG）动态的工具 细菌细胞。我们已经启动了其他研究，以阐明细菌细胞分裂的细节和 枯草芽孢杆菌中的细胞分离，我们正在寻求开发新的荧光（即， 在”）问题，这些问题将使PG合成和动力学的实时和活细菌进行研究 细胞。我们还将继续致力于循环的合成和机械研究 抑制PG生物合成的深度肽抗生素。此外，我们最近发现了数据 这表明循环深度可能具有第二种作用机理，涉及抑制 脂质回收，这是PG生物合成途径中的重要活性。脂质回收途径 还有待明确阐明，当与可能继承的双模式活动相结合时 这些循环深度正在研究，非常有希望的新途径用于识别新的 抗菌靶标和新抗菌剂的开发可能会从中出现 研究工作。 在这些领域的每个领域中的研究都需要常规访问HPLC仪器 具有多个检测模式的分辨率功能。我们当前的HPLC系统大约 二十岁，不再得到制造商的支持。此外，计算机系统 运行该乐器的要求已经过时，不再得到我们的大学的支持。作为 结果，该工具具有大量的“停机时间”，从而对研究进度产生不利影响 根据父母R35奖。在此应用程序中，我们正在寻求购买安捷伦的资金 1290 Infinity Flex系列HPLC/UHPLC仪器具有常规实用分析的能力 氨基酸，环状胡椒等以及UHPLC能力，以实现更多的分析 复杂的样品，例如PG片段。该乐器将取代我们的衰老和无法修复的 系统，显着增强我们的分析能力，并对我们的我们产生深远的积极影响 根据父母R35奖的活动。