Synthesis and Mechanistic Studies of Peptide Antibiotics

肽类抗生素的合成及机理研究

• 批准号: 6868727
• 负责人: Michael S VanNieuwenhze
• 金额: $ 23.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868727
• 关键词: antibiotics; antiinfective agents; biosynthesis; cell wall; drug design /synthesis /production; drug resistance; enzyme inhibitors; enzyme substrate complex; gram positive bacteria; lipid bilayer membrane; methicillin; nuclear magnetic resonance spectroscopy; peptide chemical synthesis; pharmacokinetics; vancomycin

DESCRIPTION (provided by applicant): Antimicrobial agents that inhibit bacterial cell wall biosynthesis have dominated treatment regimens for the management of bacterial infections for over fifty years. Glycopeptide and beta-Iactam antibiotics derive their antibacterial activity through inhibition of keys steps in the cell wall biosynthesis cascade. Bacterial resistance to these antibiotics has now reached an alarming level and has underscored the urgent need for new chemotherapeutic agents to augment the cell wall active pharmacopeia. The objective of this proposal is the chemical synthesis of three very interesting peptide antibiotics (plusbacin As, katanosin B, and mersacidin) that show very promising antibacterial activity against vancomycin-resistant and methicillin-resistant Gram-positive pathogens. These agents exert their antibiotic action via inhibition of the late-stage reactions involved in peptidoglycan biosynthesis, believed to be the result of sequestration of lipid intermediates utilized in the biosynthetic reactions. We plan to utilize our expertise in the synthesis of cell wall intermediates in order to gain structural information on the antibiotic-lipid intermediate complexes. We will also measure binding affinity of the target compounds, and their derivatives, for various lipid intermediates and attempt to correlate affinity with antibacterial activity and enzyme inhibition. Information gained from these studies will provide valuable insights regarding the function of these agents and may provide a template for de novo design of future-generation antibacterials.

描述（由申请人提供）：抑制细菌细胞壁生物合成的抗菌剂主导了治疗方案，用于治疗细菌感染已有五十多年了。糖肽和β-IACTAM抗生素通过抑制细胞壁生物合成级联中的钥匙步骤而导致其抗菌活性。对这些抗生素的细菌耐药性现在已经达到了令人震惊的水平，并强调了新的化学治疗剂迫切需要增强细胞壁活性药物。 该提案的目的是化学合成三种非常有趣的肽抗生素（Plusbacin AS，Katanosin B和Mersacidin），它们表现出对抗性霉素抗性和耐甲氧西霉素的抗甲基霉素的革兰氏阳性病原体的非常有希望的抗菌活性。这些药物通过抑制肽聚糖生物合成涉及的晚期反应来发挥其抗生素作用，被认为是生物合成反应中脂质中间体的隔离的结果。我们计划利用我们的专业知识来合成细胞壁中间体，以获取有关抗生素脂质中间体复合物的结构信息。我们还将测量目标化合物及其衍生物的结合亲和力，以实现各种脂质中间体，并试图将亲和力与抗菌活性和酶抑制相关。从这些研究中获得的信息将提供有关这些药物功能的有价值的见解，并可能为未来一代抗菌的从头设计提供模板。