Year of Award

2010

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Chemistry (Organic Option)

Department or School/College

Department of Chemistry and Biochemistry

Committee Chair

Holly Thompson

Commitee Members

Nigel D. Priestley, Michele McGuirl, Mark Cracolice, Klara Briknarova

Keywords

antibiotic, compound library, drug, natural product, nonactin, structure activity relationship

Publisher

University of Montana

Abstract

Infectious diseases will always be a public health concern. The incidence of bacterial strains found in clinical settings that exhibit resistance to our current arsenal of antimicrobial drugs has risen sharply in the past twenty years and is projected to keep rising. The Infectious Diseases Society of America (IDSA) stated that more people die of methicillin-resistant Staphylococcus aureus (MRSA) infections per year in US hospitals than HIV/AIDS and tuberculosis combined. However, stagnation of research in the area of infectious diseases over the past forty years has left us dreadfully behind in the battle against these deadly pathogens.

Recently, researchers have started getting back to the roots of drug discovery by screening possible antibiotic-producing organisms isolated from the environment. Unfortunately this will take time as many of the more common antibiotics have already been found in this manner, leaving the rarest compounds to still be found. Other drug discovery programs focus on the production of large chemical libraries by combinatorial synthesis. While hundreds of thousands of compounds have been made in this way, only one FDA approved drug has been made by de novo synthesis. Compounds made by combinatorial methods lack much of the complexity afforded by natural products. Yet, it is the complexity of natural products that makes them good antibiotics.

The strategy we employ is to use natural products in the synthesis of combinatorial libraries. In this manner, we are able to incorporate complexity into a large number of compounds, increasing our chances of finding a new compound with antimicrobial activity.

Herein is described a compound library derived from the natural product, nonactin. A preliminary library was previously synthesized by Phillips that yielded two lead compounds that were the starting points for this work. The lead compounds were systematically modified over four iterations of a Structure Activity Relationship study in an effort to maximize antimicrobial activity. Antimicrobial activity of the compounds from the SAR study against Bacillus subtilis was increased nearly 200-fold from the initial leads and spectrum of activity was expanded to include Staphylococcus aureus and Enterococcus faecalis.

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© Copyright 2010 Paul Whitney Swain III