| Note |
Thesis supervisor: Steven M. Firestine |
| Thesis |
Thesis (M.S.)--Wayne State University, 2012. |
| Summary |
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. <italic>De novo</italic> 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 N<super>5</super>-carboxy-5-aminoimidazole ribonucleotide (N<super>5</super>-CAIR). Previous studies have shown that N<super>5</super>-CAIR is a key intermediate in purine biosynthesis in bacteria, yeast and fungi, but not in humans. N<super>5</super>-CAIR is synthesized from 5-aminoimidazole ribonucleotide (AIR) by the enzyme N<super>5</super>-CAIR synthetase and it is utilized by N<super>5</super>-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 <italic>de novo</italic> purine biosynthesis inhibitors. Previous studies suggested that the isatin-based inhibitors were promising low micromolar inhibitors of N<super>5</super>-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 N<super>5</super>-CAIR mutase. |
| System Details |
Mode of access: World Wide Web. |
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System requirements: Adobe Reader. |
| Added Author |
Steven M. Firestine, advisor. |
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