CAREER: Self-assembling Nanofibers as Next Generation Antimicrobial Biomaterials

非技术部分：在医院和更广泛的环境中发现的各种抗药性微生物对普通公众、急救人员和军事人员来说是“明确和紧迫的危险”。要有效应对这一公共卫生挑战，就必须采取一种“开箱即用”的战略，从头开始设计新型的杀微生物剂。NSF职业生涯奖的目标是开发一种新型的自组装抗菌纳米纤维(SAAN)平台，与传统治疗方案相比，该平台用于更安全和更有效的抗菌肽(AMP)治疗。SAANs的系统工程将宿主细胞的细胞毒性降至最低，提高了其对蛋白酶的耐受性，并提高了其对广谱细菌的抗菌活性。拟议工作的成功将为基于AMP的抗菌疗法开辟新的途径，以治疗在民用医院和军事设施中发现的各种传染病。从拟议的研究活动中形成的基本知识将为AMP的合成和部署提供强大的基本设计原则的新词汇表。它将对专注于传统抗生素和AMP的数十亿美元的研究产生革命性影响，方法是重新设计和重新格式化多肽数据库中数千个可用的AMP，以形成SAANs，从而极大地提高它们的治疗潜力。涉及化学、微生物学、工程学、纳米科学和药学的多学科研究为培养和教育各级学生提供了充足的机会。基础生物材料设计、超分子化学和抗菌药物传递原理将融入各种研究和教育活动，特别是通过为高中生提供暑期研究机会，促进他们的科研兴趣和增强他们的职业意识。将与当地高中建立教育伙伴关系，为高中教师提供暑期研究实习机会，将拟议研究的基本知识纳入各种高中课程。技术部分：抗菌肽(AMPs)的发现为克服细菌对常用抗生素的耐药性带来了巨大的机会，因为它们直接对细菌膜起作用。然而，尽管AMPs在体外具有优异的杀菌活性，但它们对蛋白酶的敏感性、有限的循环半衰期和严重的宿主细胞毒性是其广泛应用的关键障碍。该职业奖由克拉克森大学材料研究部的生物材料项目支持，重点是自组装抗菌纳米纤维(SAANs)作为一种无载体AMP输送系统的新范例，以缓解与传统AMP相关的缺点。在SAANs中，AMP既是治疗药物，也是通过高度特异的分子间相互作用来编程和指导组装的关键结构组件。通过所提出的工作，我们将建立一个具有扩展化学功能的阳离子从头设计的多肽工具箱，用于构建各种SAANs家族，并探索新的官能团对SAANs的分子和超分子堆积、抗菌活性和血液相容性的影响。有关结构-活性关系的基础知识对于设计能够精确控制分子结构、纳米结构、刺激响应性抗菌活性和良好的生物相容性的新型抗菌纳米材料至关重要。这一提议的影响在于，SAANs可能被建立为一种新的、独特的AMP递送平台，具有明确的丝状结构，并易于将多种疗法结合起来，用于联合抗菌药物和化疗，以治疗各种人类疾病。拟议的项目将把超分子化学、生物材料设计和抗菌剂输送原则和技术与各种针对各级学生的教育和推广活动结合起来。

Non-technical section:The full range of antibiotic-resistant microbes found in hospitals and the broader environment represent a "clear and present danger" to the general public, first responders, and military personnel. Effective response to this public health challenge necessitates adoption of an "outside-the-box" strategy for the de novo design of novel classes of microbicides. The goal of this NSF Career award is to develop a novel self-assembling antimicrobial nanofiber (SAAN) platform for safer and more effective therapeutic administration of antimicrobial peptides (AMPs) compared to conventional treatment options. Systematic engineering of SAANs has minimized host cell cytotoxicity, improved their protease-resistance and their antimicrobial activity against broad-spectrum bacteria. The success of the proposed work will open new avenues for AMP-based antimicrobial therapy to treat a variety of infectious diseases found in both civilian hospitals and military facilities. The fundamental knowledge developed from the proposed research activities will provide a powerful new glossary of fundamental design principles for the synthesis and deployment of AMPs. It will have a transformative impact on the multi-billion-dollar research focused on conventional antibiotics and AMPs by re-engineering and "re-formatting" thousands of available AMPs in the peptide databank to form SAANs, thereby greatly boosting their therapeutic potential. The multidisciplinary research involving chemistry, microbiology, engineering, nanoscience, and pharmaceutical sciences provides ample opportunities to train and educate students at all levels. The fundamental biomaterials design, supramolecular chemistry and antimicrobial delivery principle will be integrated into various research and educational activities, particularly through summer research opportunities provided to high school students to promote their scientific research interests and enhance their career awareness. Educational partnership with local high school will be established to provide summer research internship to high school teachers to incorporate the fundamental knowledge of the proposed research into various high school curriculum.Technical section:The discovery of antimicrobial peptides (AMPs) has brought tremendous opportunities to overcome the prevalence of bacterial resistance to commonly used antibiotics due to their direct action against bacterial membrane. However, despite AMPs' exceptional bactericidal activity in vitro, their susceptibility to proteases, limited circulation half-lives and severe host cell toxicity represent critical hurdles to their widespread use. This CAREER award supported by the Biomaterials program in the Division of Materials Research to Clarkson University focuses on a new paradigm of Self-Assembled Antimicrobial Nanofibers (SAANs) as a vehicle-free AMP delivery system to alleviate the drawback associated with conventional AMPs. In SAANs, AMPs serve as both therapeutics and key structural components to program and direct the assembly through highly specific intermolecular interactions. Through the proposed work, we will build a toolbox of cationic de novo designed peptides with expanded chemical functionality by which to construct various SAANs families, and explore the effect of new functional groups on the molecular and supramolecular packing of SAANs, antimicrobial activity and hemocompatibility. Fundamental knowledge about the structure-activity relationship is essential for the design of new antimicrobial nanomaterials with precise control over molecular structure, nanostructure, stimuli-responsive antimicrobial activity and exquisite biocompatibility. The impact of this proposal lies in that SAANs could potentially be established as a new and unique AMP delivery platform with well-defined filamentous structure and the ease of incorporating multi-therapeutics for combinatorial antimicrobial and chemotherapy to treat various human diseases. The proposed project will integrate supramolecular chemistry, biomaterials design and antimicrobial delivery principles and techniques with various education and outreach activities for students at all levels.