Designed Antibiotic Peptides and Mimetics

设计抗生素肽和模拟物

• 批准号: 7700374
• 负责人: KEVIN H. MAYO
• 金额: $ 499.56万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7700374
• 关键词: Amino Acids; Anti-Bacterial Agents; Bacillus anthracis; Bacteria; Biological; Bioterrorism; Chemicals; Class; Communicable Diseases; Development; Dimensions; Drug or chemical Tissue Distribution; Funding; Goals; Life; Membrane; Modification; Molecular; Mus; Peptide Antibiotics; Peptides; Research Project Grants; Side; Surface; Testing; Therapeutic; Toxic effect; Yersinia pestis; bacterial resistance; bactericide; base; biodefense; design; falls; in vitro Assay; in vivo; mimetics; novel; scaffold; small molecule

The overall goal of this research project is to develop small-molecule antibacterial agents (peptides & mimetics) for use against infectious disease related to biodefense. These novel compounds fall into the bacterial membrane-disintegrating class of agents, and as such their use is not likely to promote development of bacterial resistance. The Aims of the research project are: Aim 1. Optimize bactericidal activity of the amphipathic peptide 12mer SC4. The goal is to identify key amino acids in SC4 that promote antibacterial activity, and to maximize activity with the optimal combination of amino acid side-chains and chemical modifications. Aim 2. Design calixarene-based SC4 mimetics. Amphipathic, non-peptidic compounds based on the calixarene scaffold, and molecular dimensions and surface topology of folded peptide SC4, will be designed, synthesized and tested. Information from Aim 1 will be used to guide mimetic design in Aim 2. Aim 3. Assess biological efficacy of bactericidal agents. First, all compounds made under Aims 1 and 2 will be tested in in vitro assays. The most active compounds from Aims 1 and 2 then will be tested in vivo in mice directly challenged with live bacteria. Finally, the one or two best bactericidal agents will be ADMETassessed for clearance, stability, tissue distribution and toxicity in mice. This research project has so far produced novel bactericidal agents that are effective against bioterrorism agents B. anthracis and Y. pestis, among others, and that may be developed as therapeutics.

该研究项目的总体目标是开发小分子抗菌剂（肽和 模拟物）用于对抗与生物防御相关的传染病。这些新颖的化合物属于 细菌膜崩解剂类，因此它们的使用不太可能促进 细菌耐药性的发展。该研究项目的目标是： 目标 1. 优化两亲肽 12mer SC4 的杀菌活性。目标是确定关键 SC4 中的氨基酸可促进抗菌活性，并通过最佳组合最大限度地提高活性 氨基酸侧链和化学修饰。 目标 2. 设计基于杯芳烃的 SC4 模拟物。基于的两亲性非肽化合物 将设计杯芳烃支架以及折叠肽 SC4 的分子尺寸和表面拓扑结构， 合成并测试。来自目标 1 的信息将用于指导目标 2 中的模仿设计。 目标 3. 评估杀菌剂的生物学功效。首先，根据目标 1 和 2 制造的所有化合物将 在体外测定中进行测试。然后，目标 1 和目标 2 中最活跃的化合物将在小鼠体内进行测试 直接用活细菌进行攻击。最后，将评估一种或两种最佳杀菌剂 用于小鼠体内的清除率、稳定性、组织分布和毒性。 该研究项目迄今已生产出可有效对抗生物恐怖主义的新型杀菌剂 炭疽芽孢杆菌和鼠疫耶尔森氏菌等，可开发为治疗剂。