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.

资助机会公告 (FOA) 编号：PA-20-272 最大限度地提高研究人员研究奖的设备要求 R35 136365（项目名称：化学 肽聚糖生物合成的动力学和抑制的生物学研究） 项目概要 提出这一设备要求是为了增强我们的研究能力 我们资助的 MIRA 申请代表了两者的融合。 广泛描述的针对紧急公共卫生问题的补充研究计划 我们的 MIRA 奖旨在利用我们的发现。 荧光 D-氨基酸 (FDAAs) 提供了前所未有的、迄今为止无法获得的、 用于实时、实时显示细菌细胞壁肽聚糖 (PG) 动态的工具 我们已经启动了额外的研究来阐明细菌细胞分裂和 枯草芽孢杆菌中的细胞分离，我们正在寻求开发新类别的荧光（即“转- on”）探针将能够实时研究活细菌中的 PG 合成和动力学 我们还将继续致力于循环的合成和机制研究。 此外，我们最近发现了抑制 PG 生物合成的缩酚肽抗生素。 这表明环缩肽可能有第二种作用机制，涉及抑制 脂质回收是 PG 生物合成途径中的一项重要活动。 仍有待明确阐明，并且当与可能固有的双模式活动相结合时 这些正在研究的环缩酚肽，为鉴定新的环缩肽提供了非常有前途的新途径 抗菌靶点和新抗菌剂的开发可能由此出现 研究努力。 这些领域的研究都需要常规使用具有高性能的 HPLC 仪器。 我们当前的 HPLC 系统的分辨率能力约为 已使用二十年且不再受制造商支持。此外，计算机系统。 运行该仪器所需的技术已过时，并且不再受到我们大学的支持。 结果，该仪器有大量的“停机时间”，对研究进展产生不利影响 根据母公司 R35 奖项，我们正在寻求资金购买安捷伦一台设备。 1290 Infinity Flex 系列 HPLC/UHPLC 仪器能够进行常规纯度分析 氨基酸、环肽等以及 UHPLC 功能，可分析更多 复杂的样品，例如PG碎片，该仪器将取代我们老化且无法修复的。 系统，显着增强我们的分析能力，并对我们产生深远的积极影响 母公司 R35 奖励下的活动。