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，它对手术前的消毒、手术器械的灭菌和导尿管的使用都有影响。因此，迫切需要用于金属、玻璃和塑料的抗菌涂层的新方法。与GEO Specialty Chemicals合作，主要主管最近报道了通过使用高碘酸钠的高度选择性氧化，然后与各种氨基酸反应，由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.我们将扩展这一非常有前途的合成策略，以靶向精氨酸甲基丙烯酸酯为基础的聚合物，因为精氨酸内的胍基序是众所周知的，表现出很强的抗菌活性。我们相信，用这种聚合物涂覆表面是一种令人兴奋的新治疗方法。我们还希望通过水解不稳定的亚胺键，优化含胍氯己定（GEO销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灭菌）从共聚物涂层中的缓慢释放。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，我们的全水合成路线既原子效率高，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扩大。此外，我们还计划进行探索性合成的基础上选择性氧化的羟基官能甲基丙烯酸酯前体已经生产的GEO。如果能够实现这一目标，将为新型抗菌聚合物和涂层的设计提供一种极具成本效益的技术解决方案。我们刚刚发表了我们的概念验证研究，所以这是一个非常及时的赠款提案。GEO准备生产抗菌单体/共聚物，如果它们的功效可以得到证明，并确定了合适的市场机会。因此，有可能与该公司进行未来影响案例研究。实验方法。我们将优化从GEO提供的顺式二醇甲基丙烯酸前体GEO 5 MA合成精氨酸甲基丙烯酸酯。在高碘酸盐氧化以产生双功能中间体AGE 0 5 MA后，调节水溶液pH应确保与精氨酸的席夫碱反应的最大立体特异性。我们将通过随后制备用于金属、玻璃和塑料基材的基于精氨酸甲基丙烯酸酯的共聚物涂层来扩展我们目前的研究。如果需要，我们将使用NaCNBH 3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洗必泰缀合至AGOE 5 MA的可能性。这种方法应该能够设计随时间缓慢释放氯己定的涂层，以产生高效的抗微生物涂层。将通过进行一系列抗菌试验来评价这些制剂的有效性（更多详情见下文的培训和发展计划）。合成化学将在主要主管的实验室进行，而抗菌试验将在共同主管的实验室进行。因此，博士生将接受现代合成聚合物化学的培训，并获得进行微生物测定的有用经验。