Developing Next-Generation Antimicrobial Copolymer Coatings for Biomedical Applications

背景资料。抗菌素耐药性是一个紧迫的临床问题，对手术前的消毒、手术器械的消毒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特种化学品公司合作，首席主管最近报告了通过使用高碘酸钠高度选择性地氧化顺式二醇聚合物前驱体，然后与各种氨基酸反应合成各种基于聚甲基丙烯酸氨基酸酯的聚合物(见Angewandte Chem.，2021年，60,12032-12037)。目标。我们将把这一非常有希望的合成策略扩展到以精氨酸为基础的聚合物为目标，因为众所周知，精氨酸中的胍基具有很强的抗菌活性。我们相信，在表面涂覆这种聚合物是一种令人兴奋的新治疗方法。我们还希望通过不稳定的亚胺键的水解，从共聚涂层中优化含胍的洗必泰的缓释。洗必泰是GEO销售的一种著名的广谱抗菌剂，用于对尿管等外科器械进行消毒。精氨酸聚合物的合成路线总是涉及基于保护基团化学和有机溶剂的多步骤合成，这对于商业应用来说是不划算的。相反，我们的全水相合成路线既是原子效率高的，又不涉及保护基化学。这些决定性的优势意味着，它更容易实现工业规模扩大。此外，我们还计划对GEO公司已经生产的一种羟基功能甲基丙烯酸前驱体进行选择性氧化的探索性合成。如果能够实现这一点，它将为设计新的抗菌聚合物和涂层带来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拨款建议。如果能够证明抗菌单体/共聚物的有效性，并找到合适的市场机会，GEO将准备生产它们。因此，有可能与该公司进行未来的影响案例研究。我们将优化由GEO提供的顺式甲基丙烯二醇前驱体GEO5MA合成甲基精氨酸的工艺。在高碘酸氧化生成醛功能中间体AGEO5MA后，调节水溶液的pH值应确保希夫碱与精氨酸反应具有最大的立体专一性。我们将通过随后为金属、玻璃和塑料基材制备基于精氨酸甲基丙烯酸酯的共聚涂料来扩展我们目前的研究。如果需要，我们将使用NaCNBH3来减少亚胺键，以产生更稳定的仲胺键。我们还将探索通过易水解的亚胺键将洗必泰连接到AGOE5MA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洗必泰的涂层，以产生高效的抗菌涂层。将通过进行一系列抗菌素检测来评估这些配方的有效性(详情见下文《培训和发展计划》)。合成化学将在首席监督员的实验室进行，而抗菌测试将在副监督员的实验室进行。因此，博士生将接受现代合成聚合物化学方面的培训，并获得进行微生物分析的有用经验。

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.