Toxicity Mechanism of Biocidal Conjugated Polyelectrolyte Polymers and Oligomers

ID: MPS/DMR/BMAT(7623) 1207362 PI: Chi， Eva ORG: University of New mexico标题：生物杀灭共轭聚电解质聚合物和寡聚物的毒性机制提出的研究目标是获得对一类新型合成苯乙炔（PPE）基共轭聚电解质聚合物（cpe）和具有各种细胞组件的低聚物（OPEs）之间的分子间相互作用的基本理解，这些聚合物产生了非常广泛的生物杀灭活性。这种多用途化合物的设计部分受到天然抗菌肽（amp）的启发，但具有可制造性，化学和物理稳定性以及材料应用方面的额外优势。本项目在前期研究CPEs和OPEs生物杀灭活性的基础上，重点阐明CPEs和OPEs的毒性机制，最终目的是指导具有最佳毒性和选择性的新型化合物的合理设计。cpe和OPEs本质上是阳离子和两亲性的，这使它们能够与多个细胞靶标相互作用并破坏结构，从而发挥功能。具体而言，pi计划评估具有不同链长、侧和端基、电荷密度和分布以及结构的cpe和OPEs与三种主要生物大分子组件相互作用和破坏结构的倾向：脂质膜（目标1）、蛋白质和蛋白质组件（目标2）和核酸（目标3）。为了实现这一目标，多学科团队建议使用一套生物物理和材料表征方法来研究cpe和OPEs及其细胞靶点之间的相互作用。这些研究旨在将分子结构与宏观性质联系起来，将采用模拟和分子模型来进一步了解cpe和OPEs与细胞底物在基本分子水平上相互作用的机制和性质。将这些发现与生物杀灭活性进行比较，将使pi能够阐明这类新型合成仿生材料的毒性机制和结构-功能关系。更广泛的影响：拟议的研究将阐明一类生物启发合成抗菌化合物的分子机制，这些化合物具有对抗抗生素耐药性全球威胁的潜力。阐明两亲性大分子与生物材料的分子相互作用是一项基本的科学挑战，它有可能影响许多其他领域。这些包括天然存在的amp，用于靶向药物传递和基因治疗的天然和合成细胞穿透肽，以及与神经退行性疾病发病机制有关的淀粉样蛋白。提议的研究提供了一个多学科的环境，在这个环境中，研究生和本科生将接受现代方法的训练，以解决化学、物理、工程和生物学之间的重要问题。pi致力于通过建立新的生物医学工程学位课程，并在纳米科学和微系统工程研究生课程中发挥领导作用，进一步扩大新墨西哥大学（UNM）的教育使命。他们将继续协调和参与新墨西哥大学现有的外联工作，鼓励代表性不足的群体参与，并向新的方向扩展这些现有方案。pi积极参与的现有外展项目包括：nsf材料研究与教育伙伴关系（PREM）、NSMS外展项目、本科生研究经验和西南微系统教育中心。这些项目允许pi在科学和工程的多学科方法方面培训和教育K-12，本科生和研究生以及教师。最后，pi还将把“生物工程师一天”的推广活动扩大到一所美国土著农村小学，让学生从小就对科学和工程产生兴趣。

ID: MPS/DMR/BMAT(7623) 1207362 PI: Chi, Eva ORG: University of New MexicoTitle: Toxicity Mechanism of Biocidal Conjugated Polyelectrolyte Polymers and OligomersINTELLECTUAL MERIT: The goal of the proposed research is to gain a fundamental understanding of the intermolecular interactions between a novel class of synthetic phenylene ethynylene (PPE)-based conjugated polyelectrolyte polymers (CPEs) and oligomers (OPEs) with various cellular assemblies that give rise to a remarkably broad spectrum of biocidal activity. The design of this versatile class of compounds is partly inspired by the naturally occurring antimicrobial peptides (AMPs), but with the added advantages of manufacturability, chemical and physical stability, and materials applications. Building on our previous work in characterizing the biocidal activity of the CPEs and OPEs, the project focuses on elucidating the mechanism of toxicity with the ultimate goal of guiding the rational design of novel compounds with optimal toxicity and selectivity. The CPEs and OPEs are cationic and amphiphilic in nature, which provides them the ability to interact with and disrupt the structures, and thereby functions, of multiple cellular targets. Specifically, the PIs plan to evaluate the propensity of CPEs and OPEs with varying chain length, side and end groups, charge density and distribution, and structures to interact with and disrupt the structures of three major types of biological macromolecular assemblies: lipid membranes (Objective 1), proteins and protein assemblies (Objective 2), and nucleic acids (Objective 3). To accomplish this goal, the multidisciplinary team proposes to use a suite of biophysical and materials characterization methods to study the interactions between CPEs and OPEs and their cellular targets. These studies, aimed at connecting the molecular structure with the macroscopic properties, will employ simulations and molecular modeling to gain further insights into the mechanism and nature of the interaction of CPEs and OPEs with cellular substrates at a basic molecular level. Comparing these findings with biocidal activities will enable the PIs to elucidate the toxicity mechanism and structure-function relationship of this novel class of synthetic biomimetic materials.BROADER IMPACTS: The proposed research will elucidate the molecular mechanism of a class of bioinspired synthetic antimicrobial compounds that holds the potential to combat the global threat of antibiotic resistance. Elucidation of the molecular interactions of amphiphilic macromolecules with biological materials represents a fundamental scientific challenge that has the potential to impact a number of other fields. These include naturally occurring AMPs, natural and synthetic cell penetrating peptides with applications in targeted drug delivery and gene therapy, and amyloid-forming proteins that are implicated in the pathogenesis of neurodegenerative diseases. The proposed research provides a multidisciplinary environment in which graduate and undergraduate students will be trained in modern methodologies required to address important problems at the interfaces between chemistry, physics, engineering, and biology. The PIs are committed to furthering their contributions to expanding the educational mission of the University of New Mexico (UNM) by establishing new Biomedical Engineering degree programs and by taking leadership roles in the Nanoscience and Microsystems Engineering graduate program. They will continue to coordinate and participate in existing outreach efforts at UNM that encourage the participation of under-represented groups, and to expand these existing programs in new directions. Existing outreach programs that the PIs actively engage in include: NSF-Partnership in Research and Education in Materials (PREM), NSMS outreach program, Research Experience for Undergraduates, and the Southwest Center for Microsystems Education. These programs allow the PIs to train and educate K-12, undergraduate and graduate students, and teachers in multidisciplinary methods of science and engineering. Finally, the PIs will also expand the "Bioengineer for a Day" outreach activity to a rural Native American elementary school to interest students in science and engineering at an early age.