Structure-Activity Relationships of Guanidinylated Biodegradable Antimicrobial Polycarbonates

Abstract

Given the growing threat of multidrug-resistant bacteria against conventional small molecule antibiotics, polymeric antimicrobial materials are postulated to be less susceptible to the redevelopment and regeneration of bacteria than antibiotics due to their unique physical antimicrobial mode of action. To explore the Coulombic interaction between the cationic polymer and the surface of bacterial membranes, different structural parameters were considered to systematically vary guanidinium salt functionalised aliphatic polycarbonates with different levels of molecular weights, charge densities, and amphiphilic balance through efficient post-synthesis modification via Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC) click chemistry. In addition, a new synthetic strategy on modifying the distance between the polymer backbone and guanidine group was investigated. There are three main chapters in this thesis (Chapter 3-5), which explore the different structural effects of a polymer having both antimicrobial activity and toxicity. Prior to investigating the structural effects of the polymer, Chapter 3 demonstrates the synthesis and characterisation of cyclic monomers and ring-opening polymerisation (ROP) technique to precisely control the molecular weight of the polymers. Chapter 4 reports on the molecular weight and guanidine charge density effects of polycarbonate through efficient post-synthesis modification via CuAAC click chemistry. Guanidine azide was used as an antimicrobial agent and the concept of passive diluting group is first introduced, which modifies the cationic charge density of the polymer without changing its hydrophilicity, whilst retaining a similar molecular weight of the polymer. Chapter 5 focuses on the effects of amphiphilic balance and spacer arm length between guanidine moiety and polymer backbone on the antimicrobial activity and toxicity. Based on the bioactivity results from Chapter 4, we chose the polymer with the smallest degree of polymerisation (DP) that showed the best antimicrobial activity and least toxicity as a precursor polymer to synthesise a series of copolymers, terpolymers, and different spacer arm length guanidine polymers. The overall aims of this study were achieved by lowering the minimum inhibitory and lethal concentrations of guanidinylated polycarbonates for Gram-positive and Gram-negative bacteria, and fungus with low toxicity effects against the mammalian cells.