Unraveling Bacterial Cell Wall Biosynthesis and Sensing via Synthetic Analogs

通过合成类似物解开细菌细胞壁的生物合成和传感

• 批准号: 9382168
• 负责人: Marcos M. Pires
• 金额: $ 38.69万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9382168
• 关键词: Address; Anabolism; Antibiotics; Architecture; Area; Bacteria; Bacterial Infections; Biogenesis; Cell Wall; Cells; Development; Diagnostic tests; Drug resistance; Enzymes; FDA approved; Human; Human Microbiome; Immune; Individual; Infection; Innate Immune System; Knowledge; Label; Lipids; Maintenance; Membrane; Metabolic; Neck; Organism; Pathogenesis; Patients; Phenotype; Physiology; Proteins; Public Health; Resistance; Source; Synthesis Chemistry; United States; Vesicle; analog; design; drug discovery; drug resistant bacteria; molecular recognition; new therapeutic target; next generation; novel strategies; pathogenic bacteria; receptor; resistance mechanism; response

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.

项目摘要 每年在美国，超过200万人患有细菌感染 耐FDA批准的抗生素。这些患者中有23,000多名因这种情况而死 感染。耐药细菌的迅速激增现已成为主要公众之一 21世纪的健康危机。当今使用的绝大多数抗生素被发现 几十年前。为了应对细菌的药物抗药性迅速升高，新药 迫切需要目标和诊断测试。细菌细胞壁已被证明是丰富的 抗生素药物发现的来源。但是，细菌细胞有基本方面 壁组件及其与宿主生物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构建细胞壁类似物的平台 代谢标记活细菌和模拟细胞壁结构的关键方面。我们期待 致病细菌中细胞壁重塑和加工的询问将指导 下一代抗生素的设计，这些抗生素规避了抗性机制。此外， 开发探针到系统地表征细胞壁感应和宿主分布将 将基本知识添加到细菌发病机理和人类微生物组维持中。 我们将重点关注：（1）单个酶对整体药物的贡献 表型响应活细胞细胞中的抗生素，（2）细菌的关键相互作用 膜锚定蛋白至脂质II（细胞壁生物合成的瓶颈），（3） 通过人类免疫细胞上细胞壁受体对细胞壁的分子识别，（4） 散布细菌衍生的膜囊泡的处理，其中包含细胞壁 碎片，人类免疫细胞。