Our Fall Seminar Series starts today! We welcome Dr. Steven Firestine from Wayne State University. The virtual seminar will begin at 3 p.m. today (Sept. 18) via Zoom.
Adventures in Antimicrobial Drug Discovery: Purine Biosynthesis and Spore Germination
Abstract: Antibiotics are arguably one of the greatest achievements in medical science, yet their utility is slowly being eroded by the rise of antibiotic-resistant bacteria. To combat this problem, new antibiotics focused on novel targets are desperately needed. Unfortunately, the pharmaceutical industry has divested from antimicrobial drug discovery leaving only small biotechnology companies and academia to find the next generation of antibiotics. One approach is to focus on underexplored pathways that are different between microbes and humans. Previous research has shown that the de novo purine biosynthetic pathway is different in bacteria, yeast and fungi than it is in humans. The difference is centered on the synthesis of the intermediate carboxyaminoimidazole ribonucleotide (CAIR). CAIR is synthesized from aminoimidazole ribonucleotide (AIR) and in microbes, two enzymes are required. In contrast, humans need only one enzyme. Genetic studies have shown that deleting the genes necessary for CAIR synthesis in microbes renders them avirulent. The Firestine laboratory has been focused on the interesting biochemical differences in the enzymes responsible for CAIR synthesis as well as exploiting this dissimilarity in drug discovery. The laboratory has also been exploring agents to prevent the germination of C. difficile spores. C. difficile is a challenging infection that is commonly found in hospitals and nursing homes. Spore germination is regulated by bile salts and we have discovered potent bile salt analogs which prevent germination in the nanomolar range even while in the presence of millimolar concentrations of the germinate. This seminar will outline our research on these projects.
Bio: Steve was born in Kalamazoo, MI, and attended the University of Michigan where he majored in chemistry. While at UM, Steve conducted undergraduate research in the laboratory of Dr. James Coward working on the synthesis of fluorinated leucovorin. Steve graduated UM with high honors in chemistry and joined the Department of Medicinal Chemistry and Pharmacognosy at Purdue University where he studied medicinal chemistry and biochemistry under the direction of Dr. V. Jo Davisson. His doctoral studies focused on the study of AIR carboxylase and his research showed that this enzyme was different in microbes versus humans. Steve synthesized numerous nucleoside and nucleotide analogs including NAIR, which is the most potent inhibitor of AIR carboxylase known to date. Steve graduate in 1996 and conducted a Damon Runyon Walter Winchell Postdoctoral Fellowship in the laboratory of Dr. Stephen J. Benkovic at the Pennsylvania State University. Steve conduct research into protein engineering and the generation of artificial transcriptional switches. In 2000, Steve began his independent academic career as an assistant professor of medicinal chemistry at Duquesne University in Pittsburgh, PA. There, his research focused on DNA bending agents as a mechanism to control gene expression. In 2005, Steve moved to Wayne State University and he was promoted to full professor in 2016. Since his arrival at WSU, Steve has been continuously funded by the National Institutes of Health where his research has focused on antimicrobial drug discovery.