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.
The proposed research is relevant to public health because it aims to develop a new class of antibacterial material for use in topical applications, such as those involving Staph infections of the eye. Currently, the growth in the number of antibiotic-resistant strains of bacteria is out-pacing development of new antimicrobial agents and making the treatment of many bacterial infections increasingly challenging. Therefore, 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.
|Dane, Eric L; Chin, Stacy L; Grinstaff, Mark W (2013) Synthetic Enantiopure Carbohydrate Polymers that are Highly Soluble in Water and Noncytotoxic. ACS Macro Lett 2:887-890|
|Dane, Eric L; Grinstaff, Mark W (2012) Poly-amido-saccharides: synthesis via anionic polymerization of a ýý-lactam sugar monomer. J Am Chem Soc 134:16255-64|