Developing Next-Generation Antimicrobial Copolymer Coatings for Biomedical Applications

开发用于生物医学应用的下一代抗菌共聚物涂层

• 批准号: 2825098
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2825098
• 关键词: Developing; Next; Generation; Antimicrobial; Copolymer

Background. Antimicrobial resistance is an urgent clinical problem that has ramifications for disinfection prior to surgery, sterilization of surgical instruments and use of urinary catheters. Thus new approaches for antimicrobial coatings for metals, glass and plastics are urgently required. Working with GEO Specialty Chemicals, the primary supervisor recently reported the synthesis of various poly(amino acid methacrylate)-based polymers from cis-diol polymer precursors via highly selective oxidation using sodium periodate followed by reaction with various amino acids (see Angewandte Chem., 2021, 60, 12032-12037). Objectives. We will extend this very promising synthetic strategy to target arginine methacrylate-based polymers, since the guanidinium motif within arginine is well-known to exhibit strong antibacterial activity. We believe that coating surfaces with such polymers is an exciting new therapeutic approach. We also wish to optimise the slow release of guanidinium-bearing chlorhexidine - a well-known broad-spectrum antimicrobial agent sold by GEO that is used for sterilising surgical instruments such as urinary catheters - from copolymer coatings via hydrolysis of labile imine bonds.Novelty. Synthetic routes to arginine-based polymers invariably involve multi-step syntheses based on protecting group chemistry and organic solvents, which is simply not cost-effective for commercial applications. In contrast, our wholly aqueous synthetic route is both atom-efficient and involves no protecting group chemistry. These decisive advantages mean that it is much more amenable to industrial scale-up. Moreover, we also plan to conduct exploratory syntheses based on the selective oxidation of a hydroxyl-functional methacrylic precursor already manufactured by GEO. If this can be achieved, it would result in a highly cost-effective technical solution for the design of new antimicrobial polymers and coatings.Timeliness. We have just published our proof-of-concept study, so this is a very timely grant proposal. GEO is poised to manufacture antimicrobial monomers/copolymers if their efficacy can be demonstrated and a suitable market opportunity identified. Thus there is the possibility of a future impact case study with this company.Experimental Approach. We will optimise the synthesis of arginine methacrylate from GEO5MA, a cis-diol methacrylic precursor to be provided by GEO. After periodate oxidation to generate the aldehyde-functional intermediate AGEO5MA, adjusting the aqueous solution pH should ensure maximum stereospecificity for the Schiff base reaction with arginine. We will extend our current studies by subsequently preparing arginine methacrylate-based copolymer coatings for metal, glass and plastic substrates. If required, we will reduce the imine bond using NaCNBH3 to produce a more stable secondary amine linkage. We will also explore the possibility of conjugating chlorhexidine to AGOE5MA via a hydrolytically labile imine bond. This approach should enable the design of coatings that slowly release chlorhexidine over time to produce a highly effective antimicrobial coating. These formulations will be evaluated for their efficacy by conducting a range of antimicrobial assays (see Training and Development Plan below for further details). The synthetic chemistry will be conducted in the primary supervisor's laboratory while the antimicrobial assays will be performed in the co-supervisor's laboratory. Thus the PhD student will be trained in modern synthetic polymer chemistry and also gain useful experience of performing microbiological assays.

背景。抗菌药物耐药性是一个紧迫的临床问题，对手术前的消毒、手术器械的灭菌和导尿管的使用产生影响。因此，迫切需要金属、玻璃和塑料抗菌涂层的新方法。主要主管最近与 GEO Specialty Chemicals 合作，报告了通过使用高碘酸钠进行高选择性氧化，然后与各种氨基酸反应，从顺式二醇聚合物前体合成各种聚（氨基酸甲基丙烯酸酯）基聚合物（参见 Angewandte Chem., 2021, 60, 12032-12037）。目标。我们将把这种非常有前途的合成策略扩展到基于精氨酸甲基丙烯酸酯的聚合物，因为众所周知，精氨酸中的胍基序表现出很强的抗菌活性。我们相信，用此类聚合物涂覆表面是一种令人兴奋的新治疗方法。我们还希望优化含胍氯己定（GEO 出售的一种众所周知的广谱抗菌剂，用于对导尿管等手术器械进行消毒）通过不稳定亚胺键的水解从共聚物涂层中缓慢释放的过程。新颖性。基于精氨酸的聚合物的合成路线总是涉及基于保护基化学和有机溶剂的多步骤合成，这对于商业应用来说根本不具有成本效益。相比之下，我们的全水性合成路线既具有原子效率，又不涉及保护基化学。这些决定性的优势意味着它更适合工业规模化。此外，我们还计划基于GEO已制造的羟基官能甲基丙烯酸前体的选择性氧化进行探索性合成。如果能够实现这一点，将为新型抗菌聚合物和涂层的设计带来极具成本效益的技术解决方案。时效性。我们刚刚发表了概念验证研究，因此这是一个非常及时的拨款提案。如果能够证明抗菌单体/共聚物的功效并确定合适的市场机会，GEO 准备生产抗菌单体/共聚物。因此，未来有可能对该公司进行影响案例研究。实验方法。我们将优化从GEO5MA（GEO提供的顺式二醇甲基丙烯酸前体）合成精氨酸甲基丙烯酸酯。高碘酸盐氧化生成醛功能中间体 GEO5MA 后，调节水溶液 pH 值应确保希夫碱与精氨酸反应的最大立体特异性。我们将通过随后制备用于金属、玻璃和塑料基材的精氨酸甲基丙烯酸酯共聚物涂层来扩展我们目前的研究。如果需要，我们将使用 NaCNBH3 还原亚胺键，以产生更稳定的仲胺键。我们还将探索通过水解不稳定的亚胺键将氯己定与 AGOE5MA 缀合的可能性。这种方法应该能够设计出随着时间的推移缓慢释放氯己定的涂层，从而产生高效的抗菌涂层。将通过进行一系列抗菌测定来评估这些制剂的功效（有关更多详细信息，请参阅下面的培训和开发计划）。合成化学将在主要主管的实验室中进行，而抗菌测定将在副主管的实验室中进行。因此，博士生将接受现代合成高分子化学的培训，并获得进行微生物检测的有用经验。