Publication Date

2019

Document Type

Dissertation/Thesis

First Advisor

Hagen, Timothy J.

Degree Name

M.S. (Master of Science)

Legacy Department

Department of Chemistry and Biochemistry

Abstract

Isoprenoids are a class of over 50,000 compounds that serve as key precursors for many compounds in plants and animals. These compounds play critical roles in many biological functions such as cellular growth, respiration, and go on to form critical compounds such as steroids and vitamins. Despite their overall necessity to life their biosynthesis only follows two synthetic pathways. These pathways are the Mevalonic Acid (MVA) Pathway and the 2-C-Methyl-D-Erythritol-4-Phosphate (MEP) Pathway also known as the non-mevalonate pathway. The MVA pathway is found primarily in humans and some higher plants while the MEP pathway is found in bacteria and some fungi while remaining absent in human cells. Both pathways do not share similar enzymes with each other allowing inhibition of the MEP Pathway to serve as a potential target for antimicrobial drug development. The MEP pathway consists of seven enzymes with each potentially serving as a druggable target.

This works focuses on the design, synthesis, and evaluation of inhibitors of the 2-C-Methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF) enzyme which is the fifth enzyme in MEP the pathway. Recent work in our group found that sulfonamides bind to Burkholderia pseudomallei IspF through Isothermal Titration Calorimetry, Flourescent Thermal Shift, and Saturation Transfer Difference Nuclear Magnetic Resonance. Co-crystallization structures were provided and analyzed leading to the design of various acetazolamide-based inhibitors. Compounds were then screened against both BpIspF and bCA to test for inhibitory behavior. In a separate project fluorescent compounds were designed, synthesized, and screened against BpIspF in attempts to develop a fluorescence-based high-throughput assay for IspF. These compounds resulted in single digit micromolar binding affinities for BpIspF. These compounds were then used to develop structure activity relationships to guide the synthesis of future synthetic targets.

Extent

114 pages

Language

eng

Publisher

Northern Illinois University

Rights Statement

In Copyright

Rights Statement 2

NIU theses are protected by copyright. They may be viewed from Huskie Commons for any purpose, but reproduction or distribution in any format is prohibited without the written permission of the authors.

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Text

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