Nanostructure Engineering Is Another Approach Toward Membrane-Active Antimicrobials with Desirable Activity and Selectivity

摘要# DMR ？1810767非技术总结：一种或多种传统抗生素无法抵抗的耐抗生素超级细菌正在引发公共卫生危机。膜活性抗菌剂代表了一个新的有前途的抗生素材料家族，以解决这一危机。它们包括各种各样的小分子、聚合物、多肽、自组装结构和通过破坏细菌膜杀死细菌的有机-无机杂化材料。由于这种损伤模式不针对特定的生物合成途径，因此诱导细菌耐药性的可能性大大降低。然而，目前大多数膜活性抗菌剂的设计还没有准备好应用，因为它们的疏水性被认为是打破细菌膜所必需的，也会损害哺乳动物细胞，这导致了它们不可接受的毒性。一个关键但知之甚少的问题是如何设计亲水性膜活性抗菌剂，在不破坏疏水细胞膜的情况下特异性地杀死细菌。近年来各种膜活性抗生素纳米材料的发现表明，纳米结构工程可能是开发膜活性抗菌剂的另一种途径。该奖项的目的是使材料工程、化学和生物工具适应亲水纳米结构抗生素材料的开发，并阐明纳米结构在细菌膜重塑中的作用。该奖项的成功成果将为开发具有理想活性、选择性和生物相容性的新型抗生素材料以对抗细菌耐药性的潜在范式转变铺平道路。与研究活动相结合的是一个多层次的抗微生物教育计划，该计划将提高对抗生素耐药性的广泛社会认识，并培训下一代科学家开发新的抗生素材料。该奖项的总体目标是将材料工程、化学和生物工具应用于纳米结构膜活性抗生素材料（即“纳米抗生素”）的开发，并阐明纳米结构在细菌膜重塑中的作用。核心假设是，亲水性线性链聚合物不破坏疏水膜内部，但抗菌活性差，当组装成纳米结构时，可以转化为具有高选择性的强效抗生素材料。该奖项将确定驱动这种转变的多价相互作用的作用，阐明纳米结构本身如何帮助调节抗菌活性和选择性，并确定三重选择性在纳米抗生素设计中的可行性，这些纳米抗生素将在响应环境刺激时分解并变得无活性。这一奖项将有助于打开一扇大门，将具有良好生物相容性但抗生素活性较弱的各种亲水性聚合物转化为有效的纳米结构抗生素材料。它还将揭示如何利用纳米结构膜活性抗生素材料的物理尺寸作为调整其活性和选择性的简单工具，潜在地将自下而上和自上而下纳米结构工程的最新发展纳入抗生素设计中。最后，它将研究具有拆卸“开关”的纳米抗生素的原型设计，揭示如何通过在抗生素使用后拆卸抗生素纳米结构来“按需”关闭抗菌活性，从而减少自然栖息地中残留抗生素的长期存在，这不仅有助于细菌产生耐药性，而且还会对生态系统产生不利影响。该奖项将为生物、化学、材料科学与工程等跨学科领域的博士后、研究生、本科生和K12学生提供丰富的培训机会，支持膜活性抗生素材料的教育发展，并促进社会各界对抗生素耐药性和抗生素材料的广泛认识。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Abstract # DMR ? 1810767Non-Technical Summary Antibiotic-resistant superbugs that elude one or more traditional antibiotics are causing a public health crisis. Membrane-active antimicrobials represent a new family of promising antibiotic materials to address this crisis. They include a wide variety of small molecules, polymers, polypeptides, self-assembled structures, and organic-inorganic hybrid materials that kill bacteria by disrupting bacterial membranes. Since this mode of damage does not target specific biosynthetic pathways, the possibility of inducing bacterial resistance is greatly reduced. However, most current designs of membrane-active antimicrobials are not ready for applications yet because their hydrophobicity believed to be indispensable for breaking bacterial membranes also damages mammalian cells, which gives rise to their unacceptable toxicity. A critical but poorly understood question is how to design hydrophilic membrane-active antimicrobials that kill bacteria specifically without having to breach the hydrophobic cell membrane in general. Recent discovery of various membrane-active antibiotic nanomaterials suggests that nanostructure engineering could be another approach to develop membrane-active antimicrobials. The objective of this award is to adapt materials engineering, chemistry, and biological tools for the development of hydrophilic nanostructured antibiotic materials, and to elucidate the role of nanostructures on bacterial membrane remodeling. The successful outcomes of this award will pave the way for a potential paradigm shift to develop novel antibiotic materials with desirable activity, selectivity, and biocompatibility to fight bacterial resistance. Integrated with the research activities is a multi-tiered antimicrobial education program that will bring broad societal awareness on antibiotic resistance, and train next generation of scientists on the development of new antibiotic materials. Technical SummaryThe overall objective of this award is to adapt materials engineering, chemistry, and biological tools for the development of nanostructured membrane-active antibiotic materials (i.e., "nanoantibiotics"), and to elucidate the role of nanostructures on bacterial membrane remodeling. The central hypothesis is that hydrophilic linear-chain polymers that do not breach the hydrophobic membrane interior but have poor antimicrobial activity can be transformed into potent antibiotic materials with high selectivity when assembled into nanostructures. This award will identify the role of multivalent interactions that drive this transformation, elucidate how nanostructure itself helps regulate antimicrobial activity and selectivity, and determine the feasibility of triple selectivity in the design of nanoantibiotics that will disintegrate and become inactive in response to environmental stimuli. This award will help open a door to transform diverse hydrophilic polymers that have excellent biocompatibility but weak antibiotic activity into potent nanostructured antibiotic materials. It will also reveal how to use physical dimensions of nanostructured membrane-active antibiotic materials as a simple tool to tune their activity and selectivity, potentially recruiting the latest development in both the bottom-up and top-down nanostructure engineering into antibiotic designs. Finally, it will examine a prototypical design of nanoantibiotics with dismantling "switch", shedding light on how to turn off antimicrobial activity "on demand" by disassembling antibiotic nanostructures after their service, hence reducing the prolonged presence of residue antibiotics in natural habitats that not only helps bacteria develop resistance, but also adversely impacts the ecosystems. This award will provide abundant training opportunities for postdoc, graduate and undergraduate students, and K12 participants in the interdisciplinary area of biology, chemistry, and materials science and engineering, support educational development on membrane-active antibiotic materials, and promote broad societal awareness on antibiotic resistance and antibiotic materials to diverse participants at all levels.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.