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。抗菌素耐药性是一个紧迫的临床问题，在手术前，手术仪器进行灭菌和使用尿导管的使用情况。因此，迫切需要针对金属，玻璃和塑料的抗菌涂层的新方法。主要主管使用GEO特种化学品的工作最近报道了通过高度选择性氧化使用钠含量的高度选择性氧化，从顺式二醇聚合物前体中合成了各种聚（氨基酸甲基丙烯酸酯）聚合物，然后与各种氨基酸反应（请参阅Angewandte Chem。目标。我们将将这种非常有希望的合成策略扩展到靶向基于精氨酸的聚合物，因为精氨酸中的鸟肾基序是众所周知的，众所周知，众所周知。我们认为，使用这种聚合物的涂层表面是一种令人兴奋的新治疗方法。我们还希望优化含鸟嘌呤的含鸟嘌呤含水的缓慢释放，这是GEO出售的一种众所周知的广谱抗微生物剂，用于从共聚物涂层中通过Labile imine Bonds.novelty进行灭菌。基于精氨酸的聚合物的合成途径始终涉及基于保护组化学和有机溶剂的多步合成，这对商业应用而言根本不具有成本效益。相比之下，我们的完全水性合成途径既具有原子效率，又涉及保护组化学。这些决定性的优势意味着它更适合工业规模。此外，我们还计划根据GEO已经生产的羟基功能性甲基丙烯酸前体的选择性氧化进行探索性合成。如果可以实现这一目标，将为设计新的抗微生物聚合物和涂料的设计提供高度成本效益的技术解决方案。我们刚刚发布了概念证明研究，因此这是一项非常及时的赠款建议。如果可以证明其功效并确定合适的市场机会，则GEO有望生产抗菌单体/共聚物。因此，有可能通过该公司进行未来的影响案例研究。我们将优化从GEO5MA（Geo5MA）的精氨酸甲基丙烯酸酯的合成，这是Geo提供的CIS-二醇甲基丙烯酸前体。经过周期性氧化后，产生了醛功能性的中间AGEO5MA，调整水溶液pH值应确保Schiff碱反应与精氨酸的最大立体特异性。我们将通过为金属，玻璃和塑料底物制备精氨酸甲基丙烯酸酯共聚物涂层来扩展目前的研究。如果需要，我们将使用NACNBH3减少亚胺键，以产生更稳定的二级胺连接。我们还将探索通过水解不稳定的亚胺键将氯己定结合到AGOE5MA的可能性。这种方法应该使涂层的设计随着时间的流逝而缓慢释放洗涤酰胺，以产生高效的抗菌涂层。这些配方将通过进行一系列抗菌测定法来评估其功效（有关更多详细信息，请参见下面的培训和开发计划）。合成化学将在主要主管的实验室进行，而抗菌测定法将在共同服务器实验室进行。因此，博士生将接受现代合成聚合物化学的培训，并获得进行微生物学测定的有用经验。