Synthesis and Evaluation of Antibacterial Anionic Dendritic Amphiphiles

抗菌阴离子树枝状两亲物的合成与评价

基本信息

批准号：
8265945
负责人：
Eric Lawrence Dane
金额：
$ 4.92万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8265945
关键词：
Address Adverse effects Affect Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial Eye Infections Bacterial Infections Biocompatible Biocompatible Materials Buffers Cells Clinical Treatment Corneal Injury Development Eukaryotic Cell Evaluation Eye Infections Fellowship Goals Growth Human Hydrogen Bonding In Vitro Laboratories Lead Learning Mammalian Cell Methods Molecular Structure Nanostructures Organic Synthesis Preparation Prokaryotic Cells Property Public Health Reporting Research Research Personnel Science Scientist Shapes Solutions Structure System Techniques Testing Tissues Topical application Toxic effect Training Transmission Electron Microscopy Urea Water X ray diffraction analysis X-Ray Diffraction antimicrobial drug aqueous base cytotoxic cytotoxicity design experience improved in vitro activity interest light scattering macromolecule multidisciplinary nanoscale novel repaired resistant strain small molecule success

项目摘要

DESCRIPTION (provided by applicant): In recent years, the growth in the number of antibiotic-resistant strains of bacteria has out-paced development of new antimicrobial agents. Hence, the treatment of many bacterial infections has become increasingly challenging. We propose to synthesize, characterize, and evaluate in cells a new class of anionic dendritic amphiphiles designed to have antibacterial activity towards prokaryotic cells while having minimal cytotoxic side-effects to eukaryotic cells. The preparation of new materials that act as antibacterial agents, possibly through a new mode of action, is significant because it has the potential to lead to new or improved clinical treatments for bacterial infections. In a proof-of-concept study, Grinstaff and coworkers (J. Am. Chem. Soc. 2008, 130, 14444) reported that supramolecular assemblies formed from anionic dendritic amphiphiles show antibiotic activity and minimal toxicity to eukaryotic cells. However, in order to design practical materials several needs remain. First, the ability to direct the amphiphiles into supramolecular assemblies at lower concentrations is required. We propose to introduce a hydrogen bonding core, based on a diaryl urea capable of complementary hydrogen bonding, into the amphiphiles to address this challenge. Second, the effect of the shape and size of the nanoscale assemblies on antibiotic activity and toxicity to mammalian cells needs to be better understood in order to design more effective systems. To this end, we propose to characterize the nanoscale assemblies formed by the new anionic dendritic amphiphiles (ADAs) and evaluate how these properties affect antibiotic activity in cells. We will accomplish these goals by completing the following aims: (1) Synthesize anionic dendritic amphiphiles that form supramolecular assemblies stabilized by hydrogen bonding. (2) Characterize the supramolecular nanostructures formed by the anionic dendritic amphiphiles. (3) Evaluate the supramolecular nanostructures for antibacterial activity in vitro.

描述（由申请人提供）：近年来，细菌抗生素抗性菌株数量的增长超过了新的抗菌剂的进度。因此，许多细菌感染的治疗变得越来越具有挑战性。我们建议在细胞中合成，表征和评估一种新的阴离子树突形两亲物，旨在具有对原核细胞的抗菌活性，同时对真核细胞具有最小的细胞毒性副作用。可能通过新的作用方式制备起作用的抗菌剂的新材料具有重要意义，因为它有可能导致细菌感染的新或改善临床治疗。在一项概念验证的研究中，Grinstaff及其同事（J. Am。Chem。2008，130，14444）报道说，由阴离子树突形两亲物形成的超分子组件显示出抗生素活性和对真核生物细胞的最小毒性。但是，为了设计实用材料，仍然需要一些需求。首先，需要以较低浓度将两亲物引导到超分子组件的能力。我们建议将基于能够互补氢键的日记尿素引入氢键核心，以应对这一挑战。其次，需要更好地理解纳米级组件对抗生素活性和对哺乳动物细胞毒性的影响，以设计更有效的系统。为此，我们建议表征由新的阴离子树枝状两亲物（ADA）形成的纳米级组件，并评估这些特性如何影响细胞中的抗生素活性。我们将通过完成以下目标来实现这些目标：（1）合成形成氢键稳定的超分子组件的阴离子树突形两亲物。（2）表征由阴离子树枝状两亲物形成的超分子纳米结构。（3）评估体外抗菌活性的超分子纳米结构。