Unraveling Bacterial Cell Wall Biosynthesis and Sensing via Synthetic Analogs

项目概要 在美国，每年有超过 200 万人受到细菌感染 对 FDA 批准的抗生素具有耐药性。其中超过 23,000 名患者因此死亡 感染。耐药菌迅速激增现已成为公众关注的首要问题之一 21 世纪的健康危机。当今使用的绝大多数抗生素都是被发现的 许多几十年前。为了对抗细菌耐药性的迅速上升，新药 迫切需要目标和诊断测试。细菌细胞壁已被证明具有丰富的 抗生素药物发现的来源。然而，细菌细胞有一些基本方面 壁组装及其与宿主生物体的相互作用尚未完全阐明。我们的 提出的策略将使用合成化学作为构建细胞壁类似物的平台 对活细菌进行代谢标记并模仿细胞壁结构的关键方面。我们预计 对病原菌细胞壁重塑和加工的研究将指导 设计规避耐药机制的下一代抗生素。此外， 开发系统地表征细胞壁传感和宿主分布的探针将 增加细菌发病机制和人类微生物组维护的基础知识。 我们将重点关注：（1）单个酶对整体耐药性的贡献 活细菌细胞对抗生素的反应表型，（2）细菌之间的关键相互作用 膜锚定蛋白与脂质 II（细胞壁生物合成的瓶颈点），(3) 人体免疫细胞上的细胞壁受体对细胞壁的分子识别，以及（4） 含有细胞壁的播散性细菌来源的膜囊泡的加工 碎片，由人类免疫细胞产生。

Project Summary Every year in the United States, over two million people are afflicted with bacterial infections resistant to FDA-approved antibiotics. More than 23,000 of these patients die as a result of such infections. The rapid surge in drug-resistant bacteria has now become one of the primary public health crises of the 21st century. The large majority of antibiotics in use today were discovered many decades ago. In order to counter the rapid rise in drug-resistance in bacteria, new drug targets and diagnostic tests are urgently needed. The bacterial cell wall has proven to be a rich source of antibiotic drug discovery. However, there are fundamental aspects of bacterial cell wall assembly and its interaction with the host organism that are yet to be fully elucidated. Our proposed strategies will use synthetic chemistry as a platform to construct cell wall analogs that metabolically label live bacteria and mimic key aspects of cell wall architecture. We anticipate that interrogation of cell wall remodeling and processing in pathogenic bacteria will guide the design of next-generation antibiotics that circumvent resistance mechanisms. Furthermore, the development of probes to systematically characterize cell wall sensing and host distribution will add fundamental knowledge to bacterial pathogenesis and human microbiome maintenance. We will focus on: (1) the contribution of individual enzymes to the overall drug resistant phenotype in response to antibiotics in live bacterial cells, (2) key interactions by bacterial membrane-anchored proteins to Lipid II (the bottle-neck point of cell wall biosynthesis), (3) the molecular recognition of cell wall by cell wall receptors on human immune cells, and (4) the processing of disseminated bacterial-derived membrane vesicles, which contain cell wall fragments, by human immune cells.