Multi-Target Design and Analysis of DNA-Binding Antimicrobial Peptides

DNA 结合抗菌肽的多靶点设计与分析

• 批准号: 10730319
• 负责人: Mala L Radhakrishnan
• 金额: $ 45.23万
• 依托单位: WELLESLEY COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730319
• 关键词: Address; Affinity; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Translocation; Binding; Biological Assay; Biological Testing; Cell Membrane Permeability; Cell membrane; Cells; Characteristics; Charge; Computational Technique; Computer Analysis; DNA; DNA Binding; DNA analysis; Data; Drug resistance; Electrostatics; Elements; Engineering; Equilibrium; Goals; Health; Infection; Institution; Link; Lipids; Measurement; Measures; Mediating; Membrane; Methods; Microbial Antibiotic Resistance; Modeling; Molecular; Molecular Target; Mutation; Nucleic Acids; Ownership; Pathway interactions; Peptides; Property; Proteins; Public Health; Research; Research Personnel; Resistance to infection; Series; Spectrum Analysis; Students; Surface; System; Techniques; Therapeutic; Training and Education; Variant; Vesicle; Woman; Work; antimicrobial; antimicrobial peptide; bacterial resistance; base; college; design; effective therapy; experimental analysis; experimental study; improved; insight; molecular dynamics; molecular recognition; training opportunity; undergraduate student

Antimicrobial peptides (AMPs) are a potentially promising strategy to address the ongoing health crisis of antibiotic-resistant microbial infection because they target generic bacterial structural elements, thereby rendering evolutionary pathways for bacterial resistance more difficult. Some AMPs have a hypothesized mechanism of action that first involves interacting with the bacterial cell membrane and translocating across it to enter the bacterial cell. Once these AMPs enter bacteria, they can interact with intracellular targets such as DNA. Interactions between these cationic peptides and both of their negatively-charged membrane and nucleic acid targets are mediated in large part by electrostatics. This project involves the design of AMPs with increased antimicrobial potency through rationally modifying five AMPs believed to target nucleic acids to achieve enhanced membrane and DNA binding affinity. The project workflow integrates computational techniques, such as optimization, molecular dynamics simulations, and continuum electrostatic modeling with experimental techniques, such as spectroscopy, microbiological testing, and vesicle-based assays. This multifaceted approach will allow for not only the engineering of potentially more active therapeutics but also the deeper understanding of multi-target molecular recognition in electrostatically-driven systems. Specifically, the research team will first design peptides with a range of affinities to each single target – either membrane or DNA – followed by studies to determine how binding affinity relates to antimicrobial potency and mechanism of action. Based on these results, they will then design and analyze peptides co-optimized to ideally interact promiscuously to both membrane and DNA targets. By comparing structural bases of designs resulting from different objectives, the research team will gain insight into the mechanisms of molecular recognition in this system. The project will also provide a rich cycle of computation and experiment that can be used to improve physically-based models and yield a design framework that can be applied to other peptide systems. In addition to these scientific goals, this work will focus on enhancing educational and training opportunities at Wellesley College, a women’s undergraduate-only institution. Through this research, Wellesley students will have the opportunity to take ownership of projects at the interface of computation and experiment.

抗菌胡椒（AMP）是解决该策略的潜在策略 抗生素耐药微生物感染的持续健康危机，因为它们针对 通用细菌结构元素，从而为进化途径提供 细菌抗性更加困难。一些放大器具有假设的机制 首先涉及与细菌细胞膜相互作用并易位的作用 越过它进入细菌细胞。一旦这些放大器进入细菌，它们就可以相互作用 具有细胞内靶标，例如DNA。这些阳离子肽与 它们的负荷膜和核酸靶标都介导 大部分由静电学。 该项目涉及AMP的设计，并具有增加的抗菌效力 通过合理修改五个被认为靶向核酸以实现的放大器 增强的膜和DNA结合亲和力。项目工作流程集成 计算技术，例如优化，分子动力学模拟和 使用实验技术（例如光谱）的连续静电建模， 微生物测试和基于囊泡的测定。这种多方面的方法将允许 不仅可以进行潜在更活跃的疗法的工程，而且更深层次 了解静电驱动系统中多目标分子识别。 具体而言，研究小组将首先设计具有一系列亲和力的肽 每个单个目标 - 膜或DNA，然后进行研究，以确定如何 结合亲和力与抗菌效力和作用机理有关。基于 这些结果，他们将设计和分析Petides合作以理想的相互作用 对膜和DNA靶标的混杂。通过比较 由不同目标产生的设计，研究团队将深入了解 该系统中分子识别的机制。该项目还将提供富人 可用于改善基于物理的计算和实验的循环 模型并产生可以应用于其他肽系统的设计框架。 除了这些科学目标外，这项工作还将集中于增强教育 以及韦尔斯利学院（Wellesley College）的培训机会，只有女子本科生 机构。通过这项研究，韦尔斯利学生将有机会参加 在计算和实验界面上的项目所有权。