There is an urgent need for the development of new antimicrobial agents with novel modes of action effective against drug-resistant bacteria. To that end, synthetic polymers with cationic amphiphilic properties have been designed to mimic naturally occurring host-defense antimicrobial peptides. These polymers display hallmark traits of antimicrobial peptides: broad-spectrum activity, rapid bactericidal activity, and a low propensity for resistance development in bacteria. However, while the broad-spectrum activity of these polymers is useful to eradicate all infectious pathogens, it may negatively impact commensal flora during long-term treatment. It would be ideal to develop antimicrobial polymers with cell-selective or cell-specific activity to reduce the risk of potential side effects. This thesis describes the development of cationic synthetic polymers for potent and selective Staphylococcus aureus agents, as well as investigations into their antimicrobial mechanism. Methacrylate homopolymers with primary ammonium groups in the side chains, and molecular weights of 2,000-3,000, were synthesized by reversible addition-fragmentation chain-transfer polymerization. These polymers are more active against S. aureus than E. coli without causing lysis of human red blood cells. In the presence of serum, the polymers showed potent activity against S. aureus while the activity of conventional antibiotics was reduced. Furthermore, the polymers significantly reduced the number of viable S. aureus cells in a cotton rat nasal colonization. Methacrylate homopolymers bearing primary ammonium groups in the side chains were just as active as analogous homopolymers bearing quaternary ammonium groups in the side chains. These polymers showed more potent activity against a S. aureus cell wall mutant having a higher negative charge density than the wild-type strain, indicating that electrostatic binding of the cationic polymers to anionic cell wall is an important factor in the antimicrobial mechanism of polymers. For mechanistic studies, amphiphilic methacrylate copolymers and cationic homopolymers were tested in an osmoprotection assay, with results indicating that these polymers do not exert their antimicrobial effect by osmotic lysis of bacterial cells in this condition. Overall, cationic methacrylate homopolymers without strong hydrophobic moieties can provide a new platform for anti-S. aureus agents effective in physiological conditions and insight into a previously uncharacterized mode of action for antimicrobial polymers.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/108975/1/lmthoma_1.pd
