Graduation Year

2003

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Chemistry

Major Professor

Turos, Edward.

Keywords

Drug resistant, Antibiotics, Biopolymers, MRSA, Beta-lactams

Abstract

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 beta-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 fO-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 fO-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 (fO-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.

Share

COinS