Graduation Year


Document Type




Degree Granting Department


Major Professor

Edward Turos, Ph.D

Committee Member

Julie P. Harmon, Ph..D.

Committee Member

Bill J. Baker, Ph.D.

Committee Member

Kirpal S. Bisht, Ph.D.

Committee Member

Michael W. Fountain, Ph.D.


Antibiotics, Biopolymers, MRSA, β-Lactams, Drug-Resistance


Methicillin-resistant Staphylococcus Aureus (MRSA) is now the most challenging bacterial pathogen affecting patients in hospitals and in care centers, and has brought on the need to develop new drugs for MRSA. This thesis centers on studies of N-thiolated β-lactams, a new family of potent antibacterial compounds that selectively inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA).

Chapter 1 describes MRSA in more detail. Chapter 2 outlines experiments on the effect of a fatty ester group (CO2R) on the C4-phenyl ring of N-methylthio β-lactams, expecting that attachment of long chain ester moieties might increase the hydrophobicity, and thus enhance the drugs ability to penetrate through the cell membrane. However, the results indicate that antibacterial activity drops off rapidly when more than seven carbon atoms are in the chain. These results led to the idea about examining a β-lactam conjugated polymer as a possible pro-drug delivery method, which is the focus of Chapter 3.

To synthesize the initial drug-polymer candidate, microemulsion polymerization of an acrylate-substituted lactam was done in aqueous solution to form hydrophilic polymeric nanoparticles containing the highly water-insoluble solid antibiotic, N-methylthio fO-lactam. This method has advantages over the conventional emulsion polymerization methods because a solid co-monomer (β-lactam drug) can be utilized.

SEM studies show that these polymeric nanoparticles have a microspherical morphology with nano-sizes of 40-150 nm. The N-thiolated fO-lactam containing nanoparticles display potent anti-MRSA activity at much lower drug amounts compared with free lactam drug, penicillin G or vancomycin. Although at this time the relationship between particle size and activity is not clear and the mode of action is unknown, the Nthiolated β-lactam containing nanoparticles dramatically enhance bioactivity, possibly due to increased bioavailability of the antibiotic via endocytosis.

In chapter 4, Fluorescence-active emulsified nanoparticles containing naphthyl or anthracenyl side chains were also successfully prepared by microemulsion polymerization for possible use in fluorescence studies to determine if the drug enters the cell of MRSA through endocytosis, and where possible bioaccumulation site are located.