DESIGN OF MEMBRANE-DISRUPTING ANTIMICROBIAL DRUGS

膜破坏抗菌药物的设计

• 批准号: 3142568
• 负责人: STEVEN L. REGEN
• 金额: $ 16.3万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-11-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3142568
• 关键词: amphotericin B; antibiotics; cell membrane; drug design /synthesis /production; hydropathy; osmotic pressure; sterols

The primary aim of the work that is outlined in this proposal is to develop fundamentally new principles for the rational design of antimicrobial drugs. The ultimate goal of this program is to create novel membrane-disrupting agents that can be used for the treatment of acquired immune deficiency syndrome (AIDS). A major objective of these studies is to explore sterol content, osmotic stress and bilayer curvature as 'membrane targets.' In order to obtain clear and unambiguous information, a considerable amount of effort will focus on the use of simple model systems. A second objective is to synthesize new classes of pore -forming agents that mimic the structure and function of polyene macrolide antibiotics such as amphotericin B. Specific hypotheses that are to be tested include: (i) Differences in sterol content, osmotic stress, and curvature of lipid membranes can be recognized by appropriately-designed agents and used as a basis for drug design. (ii) The recognition of sterol content, osmotic stress, and membrane curvature, can be fine-tuned by adjustment of the molecular geometry of an attacking agent. (iii) Mechanistic studies that clarify rupture and leakage pathways will greatly assist the rational design of efficacious membrane -disrupting antimicrobial drugs. Specific classes of membrane- disrupting agents that are to be synthesized include (i) amphiphiles comprised of rigid, wedge -shaped hydropbobic units attached to a hydrophilic chain, (ii) water- soluble derivatives of amphotericin B (AmpB), and (iii) amphiphilic sterol derivatives that mimic the AmpB structure. In parallel studies, the antimicrobial activity for each new compound that is to be synthesized will be evaluated and compared with its activity toward model membranes. In a broad sense, this proposal involves a combination of synthetic organic chemistry, mechanistic biomembrane studies, and in vitro antimicrobial activity measurements that is aimed at establishing fundamentally new approaches toward the design of membrane-disrupting antimicrobial agents.

这项提案中概述的工作的主要目标是 从根本上为合理设计制定新的原则 抗菌药物。这个项目的最终目标是创造 一种新型的膜破碎剂，可用于治疗 获得性免疫缺陷综合征(艾滋病)。 这些研究的一个主要目标是探索渗透的类固醇含量 应力和双层曲率作为“膜目标”。为了获得 清楚而毫不含糊的信息，大量的努力将 注重使用简单的模型系统。第二个目标是 合成模拟该结构的新型造孔剂 以及两性霉素B等多烯大环内酯类抗生素的作用。 需要检验的具体假设包括： (I)甾醇含量、渗透胁迫和弯曲度的差异 脂膜可以通过适当设计的试剂和 用作药物设计的基础。 (Ii)对甾醇含量、渗透胁迫和细胞膜的认识 曲率，可以通过调整分子的几何构型进行微调 一个攻击性特工。 (3)澄清破裂和泄漏途径的力学研究将 对高效膜破碎机的合理设计大有裨益 抗菌药物。 特定类别的膜干扰剂将被 合成的包括(I)由刚性、楔形组成的两亲化合物 与亲水链相连的疏水基团，(Ii)水溶性 两性霉素B的衍生物(AmpB)和(Iii)两亲性甾醇 模拟AmpB结构的衍生品。在平行研究中， 要合成的每一种新化合物的抗菌活性 将被评估并与其对模型膜的活性进行比较。 从广义上讲，这项提议涉及到合成的 有机化学、机械生物膜研究和体外实验 抗菌活性测量，旨在确定 膜破碎机设计的全新方法 抗菌剂。