Unraveling Bacterial Cell Wall Biosynthesis and Sensing via Synthetic Analogs

项目摘要 在美国，每年有200多万人受到细菌感染的困扰 对FDA批准的抗生素具有抗药性。其中超过23,000名患者死于这种 感染。抗药性细菌的迅速激增现在已经成为主要的公众之一 21世纪的健康危机。今天使用的绝大多数抗生素都是在 几十年前。为了对抗细菌耐药性的快速上升，新药 迫切需要目标和诊断性测试。细菌细胞壁已被证明是一种丰富的 抗生素药物发现的来源。然而，细菌细胞有一些基本的方面 壁组装及其与寄主生物体的相互作用尚未完全阐明。我们的 拟议的策略将使用合成化学作为平台来构建细胞壁类似物， 代谢性地标记活细菌并模仿细胞壁结构的关键方面。我们期待着 对病原菌细胞壁重塑和加工的询问将指导 设计下一代抗生素，绕过耐药机制。此外， 开发用于系统表征细胞壁感知和寄主分布的探针 增加细菌发病机制和人类微生物群维护的基础知识。 我们将着重于：(1)单个酶对整体耐药的贡献 活细菌细胞对抗生素的反应表型，(2)细菌的关键相互作用 膜锚定蛋白质到脂类II(细胞壁生物合成的瓶颈)，(3) 人免疫细胞上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泡的加工 由人类免疫细胞产生的碎片。

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.