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

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：肽聚糖动力学和抑制的化学生物学研究 生物合成 项目摘要 这个MIRA应用程序代表了两个互补的研究项目的融合，广泛地说， 描述，针对抗生素耐药性构成的紧迫公共卫生威胁。传染病是 抗生素是世界范围内死亡的主要原因;不幸的是，抗生素的使用提供了强大的选择性压力， 在抗生素作为治疗药物部署后不久，选择对抗生素具有抗性的菌株。而 细菌对新抗生素的抗性的选择是不可避免的，新抗生素和/或 新的抗菌目标的鉴定对于在我们与细菌的军备竞赛中保持领先至关重要。而 已经开发了针对多种细菌靶标的抗菌剂，抗菌剂的最佳靶标是 细菌的细胞壁一直是并将继续是细菌的细胞壁。此MIRA应用程序将利用我们的 荧光D-氨基酸（FDAA）的发现提供了前所未有的和迄今为止无法获得的 用于在真实的时间和活细菌细胞中可视化细菌细胞壁肽聚糖（PG）动力学的工具。 具体地说，我们提出了额外的研究，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“开启”探针，使PG合成和动力学的研究 在活的细菌细胞中进行实时检测。我们还将继续努力， 抑制PG生物合成的环缩肽抗生素的研究。此外，我们最近发现 提示环缩酚肽可能具有第二种作用机制的数据;具体地， 脂质再循环是PG生物合成途径中的一种重要活性。脂质再循环途径仍然是 清楚地阐明，当与这些环缩酚肽可能固有的双模式活性结合时， 正在研究中，非常有前途的新途径，用于鉴定新的抗菌靶标和开发 新的抗菌剂很可能从该研究努力中出现。