Candidate: Haley S. Ball
Program: Doctor of Philosophy in Biochemistry
Date of Defense: April 3, 2020
Time: 11:00 AM
Title: Development of Novel Antibiotics Targeting the First Committed Enzyme in the Methyl Erythritol Phosphate Pathway: MEP Synthase
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Meeting ID: 181 841 421
Dr. Robin Couch, Dissertation Chair
Dr. Schroeder Noble
Dr. Barney Bishop
Dr. Cynthia Dowd
Dr. John Schreifels
Abstract: The focus of this dissertation research is to develop novel antibiotics targeting the methylerythritol 4-phosphate (MEP) pathway in the following pathogenic organisms: Acinetobacter baumannii and Klebsiella pneumoniae (nosocomial pathogens), Mycobacterium tuberculosis (the causative agent of tuberculosis), Plasmodium falciparum (the causative agent of malaria), and Yersinia pestis (the causative agent of the plague). Bacteria and apicomplexan protozoans utilize the MEP pathway to synthesize isoprenoids, a class of fundamental biomolecules, with critical cellular functions including electron transport and cell wall biosynthesis. Because mammalian cells use a different biochemical pathway for isoprenoid biosynthesis, the MEP pathway is a viable target for antibiotic development. Inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (MEP synthase/IspC), the first committed enzyme of the MEP pathway, has been achieved with small phosphonic acid compounds such as fosmidomycin. Fosmidomycin suffers from bioavailability issues; however, it has been validated as an inhibitor of isoprenoid biosynthesis in vitro, and thus provides a promising scaffold for further drug development. The goals of this dissertation research are to determine structure-activity relationships (SARs) of rationally designed inhibitors based on the scaffold of fosmidomycin, elucidate the binding mechanisms of select inhibitors via enzyme assays and protein crystallization, and to assess the effect of select IspC inhibitors on targeted MEP pathway metabolite levels in bacterial cell cultures.
Congratulations to Dr. Rebecca Jones on logging another publication for the academic year. The article, “Recruiting and Enrolling Rural Students: A Model for Increasing Diversity in STEM”, is about the RADSS program, which was created from an NSF S-STEM grant.
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The Department of Chemistry & Biochemistry offers not only undergraduate programs leading to the BA and BS degree in Chemistry with optional concentrations in Biochemistry, Analytical Chemistry, and Environmental Chemistry, but also a five-year BS/Accelerated MS degree.
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