Combatting Bacterial Infections Through Polymer-Bacteria Interactions

In this dissertation, new antimicrobial functions stemming from synthetic polymer structures and properties were explored to address antibiotic resistance and tolerance in bacterial infections. Amphiphilic antimicrobial polymers that mimic host defense peptides have been explored as alternative antibiotics which could bypass existing antibiotic resistance and have a low risk of resistance development. However, their antimicrobial activity and selectivity need to be improved toward clinical use. This dissertation explored the use of macromolecules with multiple polymer chains, while the previous studies have been limited primarily to tuning monomer compositions. Since antimicrobial peptides act by collective action of multiple peptide chains, it was hypothesized that macromolecules presenting multiple antimicrobial polymer chains will show improved antimicrobial activity and selectivity towards bacteria as compared to the previously studied linear structures. Initially, we attempted to synthesize hyperbranched amphiphilic methacrylate copolymers through free radical polymerization with a crosslinking monomer (Chapter 2). However, these structures resulted in only lightly crosslinked polymers with high molecular weight, having comparable antimicrobial activity to linear polymers and increased hemolytic activity. To address the lack of target architecture, we also synthesized 4-armed star-shaped copolymers by atom transfer radical polymerization (Chapter 3). 4-armed star-shaped copolymers did not show any improved antimicrobial activity as compared to linear polymers, while they significantly increased the hemolytic activity, resulting in low selectivity. We propose future work explore architecture with additional polymer arms, which may better mimic the membrane disruptive behavior of multiple polymers on bacterial membranes. The challenge of bacterial biofilm stem from both the difficulty to prevent their formation and the difficulty to treat by traditional antibiotics, as summarized in Chapter 1. Previous anti-biofilm coatings suffer from short lifetimes, and their applications are limited to surfaces. In this dissertation, we explored a new approach to biofilm prevention based on the hypothesis that changing planktonic bacteria behavior to result in sub-optimal biofilm formation (Chapter 4). Incubation of Pseudomonas aeruginosa planktonic bacteria with a cationic polymer resulted in the aggregation of planktonic bacteria, and a reduction in biofilm development. We propose that cationic polymers may sequester planktonic bacteria away from surfaces, thereby preventing their attachment and suppressing biofilm formation. In attempts to address the antibiotic tolerance in biofilms due to low metabolic activity in bacteria, we hypothesized treatment of cationic polymers may increase the antibiotic susceptibility of embedded bacteria while the polymers are not killing bacteria by disrupting the bacterial membrane (Chapter 5). The polymer increased the metabolic activity of bacteria in biofilm and membrane potential of planktonic bacteria. These suggest that the bacteria are awaken, and antibiotic tobramycin uptake might be enhanced due to increased membrane potential. However, treatment with a cationic polymer did not increase the sensitivity of P. aeruginosa biofilms to tobramycin. While this approach does not increase biofilm sensitivity to antibiotics, it may provide the foundation for future approaches with adjuvant materials for combination therapies.PHDMacromolecular Science & EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149941/1/llfoster_1.pd