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

摘要#DMR？1810767非技术概述无法抵抗一种或多种传统抗生素的超级细菌正在造成公共健康危机。膜活性抗菌剂代表了一类新的有希望解决这一危机的抗生素材料。它们包括各种各样的小分子、聚合物、多肽、自组装结构，以及通过破坏细菌膜来杀死细菌的有机-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，目前设计的大多数膜活性抗菌剂还没有准备好应用，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。一个关键但人们知之甚少的问题是，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专门杀死细菌。最近发现的各种膜活性抗生素纳米材料表明，纳米结构工程可能是开发膜活性抗菌剂的另一种途径。该奖项的目的是应用材料工程、化学和生物工具来开发亲水性纳米结构抗生素材料，并阐明纳米结构在细菌膜重塑中的作用。该奖项的成功结果将为潜在的范式转变铺平道路，以开发具有理想活性、选择性和生物兼容性的新型抗生素材料，以对抗细菌耐药性。与研究活动相结合的是一个多层次的抗菌教育计划，该计划将带来广泛的社会对抗生素耐药性的认识，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应用材料工程、化学和生物工具来开发纳米结构的膜活性抗菌材料(即纳米抗生素)，并阐明纳米结构在细菌膜重塑中的作用。核心假设是，不破坏疏水膜内部但抗菌活性较差的亲水性直链聚合物在组装成纳米结构时可以转化为具有高选择性的高效抗菌材料。该奖项将确定推动这一转变的多价相互作用的作用，阐明纳米结构本身如何有助于调节抗微生物活性和选择性，并确定在设计纳米抗生素时三重选择性的可行性，这种抗生素将在环境刺激下解体并变得无效。该奖项将有助于打开一扇门，将具有良好生物兼容性但抗菌活性弱的各种亲水性聚合物转化为有效的纳米结构抗菌材料。它还将揭示如何将纳米结构膜活性抗生素材料的物理尺寸用作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的纳米结构工程的最新发展招募到抗生素设计中。最后，它将研究具有拆卸“开关”的纳米抗生素的原型设计，揭示如何通过在使用后拆解抗生素纳米结构来“按需”关闭抗菌活性，从而减少残留抗生素在自然栖息地的长期存在，这不仅有助于细菌产生抗药性，而且还会对生态系统产生不利影响。该奖项将为生物学、化学和材料科学与工程领域的博士后、研究生和本科生以及K12参与者提供丰富的培训机会，支持膜活性抗生素材料的教育发展，并促进各级不同参与者对抗生素耐药性和抗生素材料的广泛社会认识。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.