BIOSYNTHETIC ENZYMES OF PHOSPHONIC ACID ANTIBIOTICS

膦酸抗生素生物合成酶

• 批准号: 7843651
• 负责人: WILFRED A. VAN DER DONK
• 金额: $ 34.22万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7843651
• 关键词: Agriculture; Amino Acids; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antiparasitic Agents; Antiviral Agents; Attention; Biochemical; Biological Assay; Biological Factors; Butyric Acids; C-terminal; Catalysis; Cessation of life; Chemicals; Communicable Diseases; Complement; Development; Disease Outbreaks; Engineering; Enzymes; Epidemic; Escherichia coli; Fosfomycin; Gene Cluster; Genes; Genetic; Goals; Gram-Negative Bacteria; Health; Herbicides; Human; Immune; In Vitro; Investigation; Libraries; Methods; Methyltransferase; Multi-Drug Resistance; P-methyltransferase; Pathway interactions; Pesticides; Phosphonic Acids; Private Sector; Proteins; Reporting; Research; Resistance; Structure; System; Vitamin B 12; aminophosphonate; analog; bialaphos; cellular targeting; combinatorial; cytotoxicity; design; improved; interest; methylcobalamin-coenzyme M methyltransferase; phosphinothricin; phosphonate; prevent; programs; reconstitution; research study; synthetic protein; vinylphosphonic acid

Numerous reports of multi-drug resistant bacterial strains have appeared in recent years, with several strains posing the threat of becoming immune against all commercially available antibiotics. In order to prevent potential epidemic outbreaks of infectious diseases, a renewed focus on antibiotic research is highly desired, including the search for new natural products with alternative cellular targets, the investigation of the mechanisms of cytotoxicity and resistance, and the understanding of their biosynthetic pathways. Relatively unexplored with respect to biosynthetic pathways are phosphonate antibiotics, despite their potential use in antibacterial, antiviral, and antiparasitic therapies. Moreover, they are used extensively in agriculture as herbicides and pesticides. This project aims to biochemically characterize the biosynthetic pathways of several of these compounds including bialaphos (phosphinothricin tripeptide) and A53868 using the gene sequence information available from collaborators within this program project. Proteins will be expressed in E. coli or S. lividans and purified and their putative substrates will be chemically synthesized. In addition to elucidating the biosynthetic pathway, the mechanism of a select group of unusual enzymes will also be investigated. This project will also augment the natural phosphonates discovered by genetic studies with synthetic biased libraries that will focus on analogs of natural occurring phosphonates. The initial libraries will focus on K-26 and A53868.

近年来出现了许多有关多药耐药细菌菌株的报道，有几种菌株 构成对所有市售抗生素免疫的威胁。为了防止 潜在的传染病流行病暴发，对抗生素研究的重新关注是高度期望的， 包括搜索具有替代细胞靶标的新天然产品 细胞毒性和抗性的机制及其对生物合成途径的理解。相对地 关于生物合成途径未探索的是磷酸抗生素，尽管它们潜在使用 抗菌，抗病毒和抗寄生虫疗法。而且，它们被广泛用于农业 除草剂和农药。该项目旨在以生化为特征的生物合成途径 这些化合物中有几种使用基因（包括磷脂蛋白三肽）和A53868 该程序项目中的合作者可从合作者那里获得的序列信息。蛋白质将在 大肠杆菌或甲状腺链球菌及其推定的底物将被化学合成。此外 阐明生物合成途径，一组不寻常酶的机制也将是 调查。该项目还将增强通过遗传研究发现的自然磷酸盐 合成偏见的文库将集中于自然发生的磷酸盐的类似物。最初的库将 专注于K-26和A53868。