Novel inhibitors of the bacterial de novo purine biosynthesis enzymes, n5-carboxyaminoimidazole ribonucleotide synthetase and mutase

NOVEL INHIBITORS OF THE BACTERIAL DE NOVO PURINEBIOSYNTHESIS ENZYMES, N-CARBOXYAMINOIMIDAZOLERIBONUCLEOTIDE SYNTHETASE AND MUTASEbyMARIA V FAWAZAugust 2012 Advisor: Dr. Steven M. FirestineMajor: Pharmaceutical SciencesDegree: Master of ScienceAntibiotic resistance has seen a significant increase during the past decade. Theincreasing frequency of the drug-resistant bacterial infections has amplified the need fornovel antimicrobial agents. De novo purine biosynthesis is one area that has greatpotential for antibacterial drug development because this pathway is different inmicroorganisms versus humans. The difference in the pathway is centered on thesynthesis and utilization of the purine intermediate N-carboxy-5-aminoimidazoleribonucleotide (N-CAIR). Previous studies have shown that N-CAIR is a keyintermediate in purine biosynthesis in bacteria, yeast and fungi, but not in humans. N-CAIR is synthesized from 5-aminoimidazole ribonucleotide (AIR) by the enzyme N-CAIR synthetase and it is utilized by N-CAIR mutase to produce the intermediate 4-carboxy-5-aminoimidazole ribonucleotide (CAIR). In our laboratory we explored bothenzymes as potential targets for the design of novel de novo purine biosynthesisinhibitors. Previous studies suggested that the isatin-based inhibitors were promising lowmicromolar inhibitors of N-CAIR synthetase. Here, the biological verification of the isatincompounds as potential “hits” and their kinetic analysis are presented. The second