Developing Next-Generation Antimicrobial Copolymer Coatings for Biomedical Applications

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.