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

点击翻译按钮获取中文摘要

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.