Design and Analysis of Random Copolymers with Antimicrobial Activity

具有抗菌活性的无规共聚物的设计与分析

• 批准号: 9196509
• 负责人: SAMUEL H. GELLMAN
• 金额: $ 33.42万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196509
• 关键词: Amino Acids; Anti-Bacterial Agents; Antibiotics; Attention; Biological; Biological Assay; Catheters; Cell membrane; Cell surface; Cells; Characteristics; Charge; Chemicals; Chemistry; Clinical Treatment; Clinical Trials; Cytolysis; Data; Defense Mechanisms; Development; Diabetic Foot Ulcer; Diagnostic; Diagnostic tests; Environment; Erythrocytes; Escherichia coli; Eukaryotic Cell; Evaluation; Event; Foundations; Gastrointestinal tract structure; Generations; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Growth; Hemolysis; Hospitals; Host Defense; Human; Human body; Infection; Injection of therapeutic agent; Lead; Length; Lung; Mammalian Cell; Measurement; Membrane; Methods; Microbe; Molecular; Monitor; Nature; Nose; Nylons; Organism; Oxidative Stress; Patients; Peptides; Pharmaceutical Preparations; Phase; Polymers; Population; Prevention; Process; Production; Proteins; Reaction; Research; Resistance; S Phase; Sampling; Skin; Solid; Sterilization; Structure; Surface; Surveys; Testing; Time; Toxic effect; Ursidae Family; Variant; Vertebral column; Work; Wound Infection; analytical tool; antimicrobial; antimicrobial peptide; base; beta-Lactams; biomaterial compatibility; clinical application; combat; copolymer; cost; density; design; ear infection; fluorescence imaging; implantable device; improved; insight; interfacial; killings; large scale production; methicillin resistant Staphylococcus aureus; middle ear; mimicry; novel; pathogen; pathogenic bacteria; periplasm; polymerization; polypeptide; programs; stereochemistry

PROJECT SUMMARY The proposed work would continue a collaborative effort aimed at identifying and mechanistically characterizing new molecular strategies for combating pathogenic bacteria. Antibiotic drugs for systemic use receive the most attention in this realm. In contrast, this work focuses on novel materials that could act at interfaces between the human body and the external world. The approach, inspired by natural host- defense strategies, features an unusual combination of synthetic and novel analytical tools. Humans and other multicellular organisms deploy small antimicrobial peptides (AMPs) to protect interfaces with the external world, such as skin and the GI tract, from pathogenic bacteria. AMPs exert broad-spectrum antibacterial activity. One common mechanistic theme involves disruption of bacterial membranes. Microbes evolve resistance to this mode of action only very slowly. AMP-inspired peptides are currently in clinical trials or under consideration for treatment of diabetic foot ulcers, nasally colonized pathogens, middle ear infections, GI tract infections, lung infections, wound sterilization, and prevention of colonization of implanted devices (e.g., catheters). However, the cost of production of sequence-specific peptides is problematic for many biointerface-based applications. This research program grew out of the unconventional hypothesis that AMP activity might not require a defined subunit sequence. We have shown that sequence-random copolymers can mimic the activity profile characteristic of AMPs. Nylon-3 polymers are the focus because their protein-like backbone (-amino acid- derived subunits) promotes biocompatibility, and because considerable structural diversification can be achieved. Generation of the active materials via a polymerization process is much less expensive than the step-by-step synthetic methods that are necessary to produce sequence-specific peptides. This proposed effort includes synthesis and evaluation of many new nylon-3 copolymers with widely varying characteristics, with the goal of optimizing biological activity profiles and laying a foundation for biomedical applications. The copolymers comprise a mixture of hydrophilic and hydrophobic subunits. Unexpected results from recent studies of hydrophobic subunit variation lead us to propose a parallel study of cationic subunit variation. Our distinctive single-cell measurements will be adapted to allow us to survey large numbers of new polymer samples. A new aspect of the program will use solid-phase polypeptide synthesis in a novel way to prepare subsets of the diverse chain populations generated via polymerization reactions. Assessing these "submixtures" by conventional and single-cell methods should provide unprecedented insight into relationships between polymer structure and biological activity. This work will deepen our mechanistic understanding of nylon-3 polymer activity and ultimately lead us to new polymer compositions that manifest improved antibacterial activity and prokaryotic vs mammalian cell selectivity.

项目摘要 拟议的工作将继续开展协作， 描述了对抗病原菌的新分子策略。抗生素类药物 在这个领域中，使用受到了最多的关注。相比之下，这项工作的重点是新的材料， 在人体和外部世界之间的界面。这种方法的灵感来自于自然宿主- 防御战略，具有合成和新颖的分析工具的不寻常的组合。 人类和其他多细胞生物利用小的抗菌肽（AMP）来保护 与外界接触，如皮肤和胃肠道，免受病原菌的侵害。AMP发挥 广谱抗菌活性。一个常见的机制主题涉及破坏细菌 膜。微生物对这种作用模式的抗性发展非常缓慢。AMP激发的肽是 目前在临床试验中或正在考虑用于治疗糖尿病足溃疡，鼻定植 病原体、中耳感染、胃肠道感染、肺部感染、伤口消毒和预防 植入装置的定殖（例如，导管）。然而，序列特异性的生产成本 肽对于许多基于生物界面的应用是有问题的。 这项研究计划起源于一个非传统的假设，即AMP活性可能不需要一个 定义的亚基序列。我们已经表明，序列无规共聚物可以模仿的活动概况 AMP的特性。尼龙-3聚合物是焦点，因为它们的蛋白质样骨架（β-氨基酸- 衍生的亚基）促进生物相容性，并且因为相当大的结构多样化可以是 办妥了一批通过聚合方法产生活性材料比通过聚合方法产生活性材料便宜得多。 逐步合成方法是生产序列特异性肽所必需的。 这项工作包括合成和评价许多新的尼龙-3共聚物， 不同的特性，以优化生物活性谱和奠定基础， 生物医学应用共聚物包含亲水和疏水亚单元的混合物。 最近疏水亚基变异研究的意外结果使我们提出了一个平行的研究 阳离子亚基的变异。我们独特的单细胞测量将被调整， 大量新的聚合物样品。该计划的一个新方面将使用固相多肽 以新的方式合成以制备通过聚合产生的不同链群的子集 反应.通过常规和单细胞方法评估这些“亚混合物”， 对聚合物结构和生物活性之间关系的前所未有的洞察。这项工作将 加深我们对尼龙-3聚合物活性的机理理解，并最终引导我们开发新的聚合物 这些组合物表现出改善的抗菌活性和原核细胞对哺乳动物细胞的选择性。