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

• 批准号: 10597980
• 负责人: Michael S VanNieuwenhze
• 金额: $ 37.56万
• 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/10597980
• 关键词: Address; Amino Acids; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus subtilis; Bacteria; Biology; Cause of Death; Cell Separation; Cell Wall; Cell division; Cells; Chemicals; Communicable Diseases; Coupled; Cyclic Peptides; Cyclodepsipeptides; Data; Depsipeptides; Development; Lipids; Pathway interactions; Peptide Antibiotics; Peptidoglycan; Polymers; Polysaccharides; Public Health; Recycling; Research; Therapeutic; Time; Visualization software; arms race; bacterial resistance; novel; polymerization; pressure; programs; resistant strain; Address; Amino Acids; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus subtilis; Bacteria; Biology; Cause of Death; Cell Separation; Cell Wall; Cell division; Cells; Chemicals; Communicable Diseases; Coupled; Cyclic Peptides; Cyclodepsipeptides; Data; Depsipeptides; Development; Lipids; Pathway interactions; Peptide Antibiotics; Peptidoglycan; Polymers; Polysaccharides; Public Health; Recycling; Research; Therapeutic; Time; Visualization software; arms race; bacterial resistance; novel; polymerization; pressure; programs; resistant strain

PROJECT TITLE: Chemical Biology Studies of the Dynamics and Inhibition of Peptidoglycan Biosynthesis PROJECT SUMMARY This 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. Infectious diseases are the leading cause of death world-wide; unfortunately, antibiotic use provides a strong selective pressure that results in the selection of strains that are resistant to the antibiotic shortly after its deployment as a therapeutic. While the selection of bacterial resistance to new antibiotics is inevitable, the development of new antibiotics and/or the identification of new antibacterial targets is essential to stay ahead in our arms race with bacteria. While antibacterial agents have been developed against multiple bacterial targets, the best target for antibacterial development has been, and continues to be, the bacterial cell wall. This MIRA application will 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. Specifically, we propose additional studies to elucidate the details of bacterial cell division and cell separation in Bacillus subtilis, and we will develop “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; specifically, 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.

项目名称：动力学和抑制肽聚糖的化学生物学研究 生物合成 项目摘要 此MIRA应用代表了两个完整的研究计划的融合 描述的是，针对抗生素耐药性构成的URGET公共卫生威胁。传染病是 全球死亡的主要原因；不幸的是，抗生素的使用提供了强大的选择性压力 在选择抗生素作为治疗后不久对抗生素具有抗性的菌株。尽管 不可避免地选择对新抗生素的细菌耐药性，新抗生素的发展和/或 鉴定新的抗菌靶标对于在我们使用细菌的军备竞赛中保持领先地位至关重要。尽管 已经开发了针对多种细菌靶标的抗菌剂，这是抗菌的最佳靶标 开发一直并继续是细菌细胞壁。此Mira应用程序将利用我们的 发现前所未有的荧光D-氨基酸（FDAA） 实时和活细胞细胞中可视化细菌细胞壁胡椒糖（PG）动力学的工具。 具体而言，我们提出了其他研究，以阐明细菌细胞分裂和细胞分离的细节 枯草芽孢杆菌，我们将开发“上交”问题，这些问题将使PG合成和动力学研究 实时和活细胞中。我们还将继续致力于综合和机械的努力 抑制PG生物合成的环状深度psipeptide抗生素的研究。此外，我们最近发现了 表明循环深度可能具有第二种作用机理的数据；具体而言，抑制 脂质回收，这是PG生物合成途径中的重要活性。脂质回收途径仍然是 明确阐明并与可能是这些环状深度固有的双模式活动结合在一起 在研究中，非常承诺确定新的抗菌靶标的新途径 这项研究工作可能会出现新的抗菌剂。