Synthesis and Mechanistic Studies of Peptide Antibiotics

描述(由申请人提供)：50多年来，抑制细菌细胞壁生物合成的抗菌剂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反应中的关键步骤而获得抗菌活性。细菌对这些抗生素的抗药性现在已经达到了令人震惊的水平，并突显了迫切需要新的化疗药物来增强细胞壁活性药典。 这些药物通过抑制参与肽聚糖生物合成的后期反应来发挥其抗菌作用，据信这是生物合成反应中所用的脂中间体被隔离的结果。我们计划利用我们在细胞壁中间体合成方面的专业知识来获得抗生素-脂质中间体复合体的结构信息。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，并试图将亲和力与抗菌活性和酶抑制联系起来。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，并可能为未来一代抗菌药的从头设计提供模板。

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.