Date of Award

8-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Medicinal Chemistry

Research Advisor

Richard Lee, Ph.D.

Committee

Peter Bridson, Ph.D. Duane D Miller, Ph.D. P. David Rogers, Ph.D. Stephen W White, D.Phil.

Keywords

Antibiotics, Drug Discovery, Medicinal Chemistry

Abstract

As a species, humans have become ever reliant on the use of antibiotics to facilitate our everyday lives. The widespread emergence of resistance to currently used antibiotics is commonly attributed to an over use in our society. Such resistance, coupled with a lack of innovation and production of novel antibiotic drugs, threatens to return humanity to an era similar to one before the discovery of the first antibiotics. The need to find new agents to be used in this fight is paramount, as well as learning from our recent failures to produce such compounds. This document will highlight my efforts to contribute to the field of antibiotic drug discovery from a medicinal chemist’s perspective. Chapter one will be a brief survey of the current state of antibiotics. There will be a brief description of various classes of drugs used and some of their pharmacology. The second chapter will focus on the specific field of drug discovery for the pathogen Mycobacterium tuberculosis, and some of the difficulties associated with targeting this particular organism. This includes two classes of inhibitors that have distinct mechanisms of action from commonly used anti-tubercular compounds. These series have

distinctly different paths to clinical relevance; one seeks improved drug-like properties and the other seeks unique potency at an old target. The third chapter highlights a structure guided design of new anti-folate compounds, a reinvestigation of known inhibitors of this biosynthetic pathway and exploratory repurposing of compounds active against malaria. This chapter also holds a section on chemical repurposing, a technique becoming increasingly useful in the field of antibiotic discovery. The fourth and final chapter will be a synopsis and recollection of my graduate work and on the field of antibiotic drug discovery in general.

ORCID

http://orcid.org/0000-0001-7260-4522

DOI

10.21007/etd.cghs.2016.0459

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