Synthesis and Mechanistic Studies of Peptide Antibiotics

肽类抗生素的合成及机理研究

• 批准号: 7149128
• 负责人: Michael S VanNieuwenhze
• 金额: $ 11.97万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149128
• 关键词: Affinity; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Cell Wall; Class; Complex; Depsipeptides; Environment; Enzyme Inhibition; Future Generations; Glycopeptides; Infection; Lipid Bilayers; Lipids; Measures; Methicillin Resistance; Multi-Drug Resistance; Peptide Antibiotics; Peptides; Peptidoglycan; Pharmaceutical Preparations; Pharmacopoeias; Reaction; Research; Research Proposals; Resort; Shotguns; Staging; Staphylococcus aureus; Structure; Treatment Efficacy; Treatment Protocols; Urination; Vancomycin; Vancomycin Resistance; Vancomycin resistant enterococcus; antimicrobial drug; chemical synthesis; chemotherapeutic agent; design; insight; interest; katanosin B; lanthionine; mersacidin; pathogen; plusbacin A3

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药物在50多年来一直主导着细菌感染的治疗方案。糖肽和β -内酰胺类抗生素通过抑制细胞壁生物合成级联中的关键步骤而获得抗菌活性。细菌对这些抗生素的耐药性现在已经达到了惊人的水平，并强调了迫切需要新的化疗药物来增加细胞壁活性药典。