Biosynthesis of nucleoside antibiotics targeting bacterial translocase

针对细菌转位酶的核苷抗生素的生物合成

• 批准号: 8465172
• 负责人: Steven Gary Van Lanen
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465172
• 关键词: 3-hydroxybutanal; Acquired Immunodeficiency Syndrome; Amino Acids; Anabolism; Animals; Anti-Bacterial Agents; Antibiotics; Bacteria; Biochemical; Biochemical Reaction; Biological Assay; Biological Factors; Carbon; Case Study; Cell Wall; Cessation of life; Clinic; DNA Fingerprinting; Development; Disease; Drug resistance; Drug resistance in tuberculosis; Enzymes; Family; Fluorescence; Gene Silencing; Generations; Genes; Genetic; Genotype; Glycine Hydroxymethyltransferase; Goals; Health; Hexoses; Hospitals; Human; In Vitro; Infection; Libraries; Modeling; Modification; Multi-Drug Resistance; Natural Product Drug; Nucleosides; Parents; Peptidoglycan; Pharmaceutical Preparations; Physical condensation; Property; Public Health; Reaction; Recombinant Proteins; Research; Streptomyces; Structure-Activity Relationship; System; Testing; Tuberculosis; United States; base; biomaterial compatibility; combinatorial; community setting; design; drug discovery; expectation; improved; in vivo; inhibitor/antagonist; killings; methicillin resistant Staphylococcus aureus; novel; pathogen; scaffold; sugar; tool; translocase

DESCRIPTION (provided by applicant): The emergence of multiple drug resistant pathogens is becoming problematic worldwide, and the discovery of new antibiotics continues to decline. The broad, long-term objective of this proposal is to discover, characterize, and develop a new structural class of antibiotics-nucleoside antibiotics-that target bacterial translocase I involved in peptidoglycan cell wall biosynthesis. The specific aims of this proposal are (I) to characterize the assembly and incorporation of the aminoribosyl moiety found within the family of lipopeptidyl-nucleoside antibiotics and (II) to functionally and mechanistically characterize enzymes catalyzing novel or unusual biochemical reactions represented herein by a new family of serine hydroxymethyltransferase-like enzymes that are hypothesized to catalyze an aldol-type condensation to form unusual nonproteinogenic amino acids. Specific Aim I and II will be achieved by using the robust genetic system developed for the lipopeptidyl nucleoside A-90289-producing strain for in vivo studies employing gene inactivation and cross-complementation, and recombinant proteins will be exploited for functional and mechanistic studies in vitro. The results will establish a new mechanism for incorporating ribosyl units into natural product scaffolds and will establish a paradigm for the entry into high-carbon nucleoside antibiotics. The results will be essential for our long-term goals of searching for new nucleoside antibiotics using genetic information (a genotype-to-chemotype approach), will allow for the structural diversification of the parent scaffolds using combinatorial biosynthesis and total synthesis, and will provide the basis for the design of second generation antibiotics with improved biocompatibility and pharmacological properties.

描述（由申请人提供）：多种耐药病原体的出现在全球范围内变得有问题，新抗生素的发现仍在下降。该提案的广泛长期目标是发现，表征和开发一种新的结构性抗生素核苷抗生素 - 靶向细菌易位酶I参与肽聚糖细胞壁生物合成。该提案的具体目的是（i）表征在脂肽基部分中发现的氨基糖基部分的组装和合并，在脂肽基核苷抗生素和（ii）中，（ii）在功能上和机械上表征了催化新颖或不寻常的生物学反应，以新的或不寻常催化藻型冷凝，形成异常的非蛋白质生成氨基酸。具体目标I和II将通过使用为脂肽核苷A-90289产生的鲁棒遗传系统用于体内研究中产生基因失活和交叉补充的体内研究，重组蛋白将被利用用于玻璃体的功能和机械研究。结果将建立一种将核糖基单元掺入天然产物支架中的新机制，并将建立进入高碳核苷抗生素的范式。结果对于我们使用遗传信息（一种基因型对化学方法）搜索新的核苷抗生素的长期目标至关重要，将允许使用组合型生物合成和总合成对父型支架的结构多样化，并将为具有改善生物学性质的第二代抗生素设计提供基础。