Chemical Biology Studies of the Dynamics and Inhibition of Peptidoglycan Biosynthesis

项目名称：肽聚糖动力学和抑制作用的化学生物学研究 生物合成 项目总结 这个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，针对抗生素耐药性构成的紧迫公共健康威胁。传染病是 世界范围内的主要死亡原因；不幸的是，抗生素的使用提供了强大的选择压力，导致 在抗生素作为治疗药物部署后不久，在选择对其产生抗药性的菌株方面。而当 细菌对新抗生素的耐药性选择是不可避免的，新抗生素的开发和/或 识别新的抗菌目标对于我们在与细菌的军备竞赛中保持领先至关重要。而当 针对多个细菌靶点的抗菌剂已经开发出来，这是抗菌的最佳靶点 发展一直是，并将继续是细菌的细胞壁。这款Mira应用程序将利用我们的 荧光D-氨基酸(FDAAs)的发现，提供了前所未有的和迄今无法获得的 用于实时和在活细菌细胞中可视化细菌细胞壁肽聚糖(PG)动态的工具。 具体地说，我们建议进行更多的研究，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，这将使PG的合成和动力学研究成为可能 在实时和活的细菌细胞中。我们还将继续努力，针对综合和机械 抑制PG生物合成的环肽类抗生素的研究。此外，我们最近还发现了 数据表明，环状脱脂肽可能有第二种作用机制；具体地说，抑制 脂循环，PG生物合成途径中的一项重要活动。脂类循环途径尚待解决 清楚地阐明，当与这些环状脱肽可能固有的双模活性结合时 正在研究中，非常有希望的新途径，以确定新的抗菌目标和开发 新的抗菌剂很可能会从这项研究中出现。

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.