Synthesis and Mechanistic Studies of Peptide Antibiotics

肽类抗生素的合成及机理研究

• 批准号: 6986205
• 负责人: Michael S VanNieuwenhze
• 金额: $ 34.28万
• 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/6986205
• 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）：五十多年来，抑制细菌细胞壁生物合成的抗菌剂一直主导细菌感染的治疗方案。糖肽和 β-内酰胺抗生素通过抑制细胞壁生物合成级联中的关键步骤来获得抗菌活性。细菌对这些抗生素的耐药性现已达到惊人的水平，并强调迫切需要新的化疗药物来增强细胞壁活性药典。 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），它们对万古霉素耐药和甲氧西林耐药革兰氏阳性病原体显示出非常有前景的抗菌活性。这些药物通过抑制肽聚糖生物合成中涉及的后期反应来发挥抗生素作用，这被认为是生物合成反应中使用的脂质中间体螯合的结果。我们计划利用我们在细胞壁中间体合成方面的专业知识，以获得抗生素-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与各种脂质中间体的结合亲和力，并尝试将亲和力与抗菌活性和酶抑制相关联。从这些研究中获得的信息将为这些药物的功能提供有价值的见解，并可能为下一代抗菌药物的从头设计提供模板。