Date of Degree

2-2015

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor(s)

Nan-Loh Yang

Subject Categories

Chemistry | Polymer Chemistry

Abstract

The increasing prevalence of antibiotic resistant bacteria (superbugs) has created a pressing need for new systems of antimicrobial agents. In this dissertation, I report on my extensive research on the design, synthesis, and development of synthetic amphiphilic macromolecules with antimicrobial activity and very low hemolytic impact. Synthetic amphiphilic polymers attack bacteria directly to rupture the cell membrane through electrostatic and hydrophobic interactions. However, the toxicity of such synthetic amphiphilic polymers against mammalian cells have impeded their therapeutic applications. We investigated the systematic structure/activities relationships for antibacterial and hemolytic activities of amphiphilic polyacrylates and poly(vinyl esters). Acrylate homopolymers with various lengths of alkyl pendant groups displayed high antibacterial activity against Staphylococcus aureus (S. aureus) and very low hemolytic activity toward red blood cells (RBCs). In comparison with polyacrylate homopolymers, random copolymers were highly antibacterial but extremely hemolytic. To further improve antibacterial activity of polyacrylates, while maintaining low hemolytic activity, a series of copolymers with 2-carbon and 6-carbon spacer arm (distance between polymer backbone and cationic center) counits were investigated. Our strategy of controlling charge distribution and mole ratios of 2-carbon (M2) and 6-carbon counits (M6) resulted in a polymer with >200 fold selectivity toward Escherichia coli (E. coli) over RBCs. Copolymerization of just 10 mole% of shorter spacer arm M2 counits with hydrophobic M6 counits led to a drastic reduction in hemolytic activity by a factor of 850 compared with highly hemolytic M6 homopolymer, without severe deterioration of antibacterial activity. Scanning electron microscopy analysis of bacterial cells established the membrane rupture action of these polymers.

In a second acrylate system, hydrophilic and biocompatible poly(ethylene glycol) (PEG) monomers were copolymerized with M6 monomer to achieve selective (bacteria over RBCs) antibacterial activity in polymers. Incorporation of 30 mole% of PEG monomer led to a polymer with >100 times selectivity toward E. coli over RBCs. The Hydrogen-bonding ability of the PEG segments plays significant roles.

For a third system of poly(vinyl ester), we explored the role of hydrophobic side groups, molecular weight, and amphiphilicity on its activities.

This dissertation investigation has led to one of the most promising synthetic polymer systems reported till today for antimicrobial applications.

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