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Access Type

WSU Access

Date of Award

January 2012

Degree Type

Thesis

Degree Name

M.S.

Department

Pharmaceutical Sciences

First Advisor

Steven M. Firestine

Abstract

Antibiotic resistance has seen a significant increase during the past decade. The increasing frequency of the drug-resistant bacterial infections has amplified the need for novel antimicrobial agents. De novo purine biosynthesis is one area that has great potential for antibacterial drug development because this pathway is different in microorganisms versus humans. The difference in the pathway is centered on the synthesis and utilization of the purine intermediate N5-carboxy-5-aminoimidazole ribonucleotide (N5-CAIR). Previous studies have shown that N5-CAIR is a key intermediate in purine biosynthesis in bacteria, yeast and fungi, but not in humans. N5-CAIR is synthesized from 5-aminoimidazole ribonucleotide (AIR) by the enzyme N5-CAIR synthetase and it is utilized by N5-CAIR mutase to produce the intermediate 4-carboxy-5-aminoimidazole ribonucleotide (CAIR). In our laboratory we explored both enzymes as potential targets for the design of novel de novo purine biosynthesis inhibitors. Previous studies suggested that the isatin-based inhibitors were promising low micromolar inhibitors of N5-CAIR synthetase. Here, the biological verification of the isatin compounds as potential "hits" and their kinetic analysis are presented. The second project involves the discovery, kinetic evaluation, molecular modeling, and exploratory synthesis of the first known, selective inhibitor of N5-CAIR mutase.


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