Novel Polymer-Based Materials for Combating Bacterial Biofilms

Abstract

Bacteria are well known to form multicellular communities known as biofilms, which contribute to their survival in harsh environments including infection sites where they resist the host immune defences and most antimicrobial agents. The overall goal of this thesis was to develop and evaluate polymer-based materials that possess activity against bacterial biofilms for overcoming antibiotic resistance and improving biofilm-related infection treatments. In this thesis, three different approaches were explored. First, new antimicrobial polymers were developed that displayed promising characteristics for combating biofilms. Initially, linear random copolymers consisting of oligoethylene glycol, amine, and hydrophobic groups were made using RAFT polymerisation. These copolymers underwent self-folding in aqueous media due to intramolecular hydrophobic interactions to form single-chain polymeric nanoparticles (SCPNs). The resulting SCPNs showed potent activity against Gram-negative bacteria and good biocompatibility with mammalian cells. Remarkably, the SCPNs killed 99.99% of both Pseudomonas aeruginosa biofilm and planktonic cells within an hour. In a second approach, nitric oxide (NO) gas was selected for its ability to provoke the dispersal of resistant biofilms. Polymeric nanoparticles for the co-delivery of NO and the antibiotic gentamicin were developed and revealed to have potent anti-biofilm activity. The manipulation of gentamicin, a clinically relevant drug, to create an NO-releasing moiety was a novel feature of this work. The gentamicin-NO nanoparticles were shown to effectively disperse biofilms, and strongly reduced the viability of both P. aeruginosa biofilm and planktonic cells by 90% and 95%, respectively. In a third approach, iron oxide nanoparticles (IONPs) that induced local hyperthermia in the presence of a high-frequency magnetic field were developed and shown to be useful adjuvants for antibiotic-mediated clearance of P. aeruginosa biofilms. While bare IONPs rapidly formed aggregates, polymer-stabilised IONPs remained well dispersed in solution during the magnetic induction. It was found that the heat generated by polymer-stabilised IONPs was effective at dispersing pre-formed biofilms in a non-toxic manner. Also, combined treatments of polymer-stabilised IONPs and the antibiotic gentamicin showed a 4.1- and 3.2-fold increase in their efficacy against P. aeruginosa biofilm and planktonic cells, respectively, compared to gentamicin alone.