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 项目概要 该 MIRA 应用程序代表了两个互补研究项目的融合，这两个项目大体上是 描述的，针对抗生素耐药性造成的紧迫公共卫生威胁。 不幸的是，抗生素的使用产生了强大的选择压力，导致 在抗生素作为治疗药物使用后不久就选择对其具有抗药性的菌株。 细菌对新抗生素产生耐药性的选择是不可避免的，新抗生素的开发和/或 确定新的抗菌靶点对于在细菌军备竞赛中保持领先地位至关重要。 针对多种细菌靶点已开发出抗菌剂，是抗菌的最佳靶点 细菌细胞壁的发展一直是，并且将继续是，这个 MIRA 应用程序将利用我们的技术。 荧光 D-氨基酸 (FDAAs) 的发现提供了前所未有的且迄今为止无法获得的 用于在活细菌细胞中实时可视化细菌细胞壁肽聚糖（PG）动态的工具。 具体来说，我们建议进行额外的研究来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“启动”探针，以便研究 PG 合成和动力学 我们还将继续致力于合成和机制研究。 此外，我们最近发现了抑制 PG 生物合成的环缩酚肽抗生素的研究。 数据表明环缩肽可能具有第二种作用机制，具体来说，是抑制 脂质回收，PG生物合成途径中的一个重要活性脂质回收途径仍有待进一步研究。 明确阐明，并且当与这些环状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，用于识别新的抗菌靶点和开发 这项研究工作可能会出现新的抗菌剂。