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.

抗菌肽(AMP)是一种潜在的有希望的策略来解决 持续的抗药性微生物感染的健康危机，因为他们的目标是 通用细菌结构元素，从而为 细菌耐药性变得更加困难。一些AMP有一种假设的机制 首先涉及与细菌细胞膜相互作用和移位的作用 穿过它进入细菌细胞。一旦这些AMP进入细菌，它们就可以相互作用 细胞内的靶标，如DNA。这些阳离子多肽与蛋白质之间的相互作用 它们的带负电的膜和核酸靶标都介导在 很大程度上是由静电作用造成的。 该项目涉及增加抗菌效力的AMP的设计。 通过合理修饰五个据信靶向核酸的AMP来实现 增强了膜和DNA的结合亲和力。项目工作流集成了 计算技术，如最优化、分子动力学模拟和 使用实验技术的连续介质静电模拟，例如光谱学， 微生物检测和基于囊泡的检测。这种多方面的方法将允许 不仅是潜在的更活跃的治疗方法的工程，而且还有更深层次的 理解静电驱动系统中的多目标分子识别。 具体地说，研究小组将首先设计具有一系列亲和力的多肽 对每个单一的靶--膜或DNA--进行研究，以确定如何 结合亲和力与抗菌剂的效力和作用机制有关。基于 这些结果，然后他们将设计和分析共同优化的多肽，以理想地相互作用 混杂地作用于膜和DNA靶标。通过比较以下结构基础： 不同目标产生的设计，研究团队将深入了解 该体系中的分子识别机制。该项目还将提供丰富的 计算和实验的循环，可用于改善基于物理的 模型，并产生可应用于其他多肽系统的设计框架。 除了这些科学目标外，这项工作还将侧重于加强教育 和韦尔斯利学院的培训机会，这是一所仅限女性本科生的学院 机构。通过这项研究，卫尔斯理的学生将有机会 在计算和实验的界面上拥有项目所有权。