Date of Award

Winter 2021

Project Type

Dissertation

Program or Major

Chemistry

Degree Name

Doctor of Philosophy

First Advisor

Marc A Boudreau

Second Advisor

Arthur Greenberg

Third Advisor

Charles K Zercher

Abstract

Antibiotics are important substances that have been used in clinical treatment for over 70 years. Because of overuse and misuse of antibiotics, bacteria developed resistance. However, bacterial resistance towards antibiotics, especially the β-lactam antibiotics, is becoming increasingly threat. Currently, the β-lactam antibiotics are seriously threatened by β-lactamases. Metallo-β-lactamases (MBLs), a sub-class of β-lactamases, have been found in several bacteria since they confer resistance to many different β-lactams, and as a result, the bacteria survive in their presence. A potential treatment is to synthesize inhibitors of MBLs, however, there are no inhibitors synthesized in clinical use. The goal of this project is to synthesize a series of thioacids and dicarboxylic acids derived from open β-lactams, which are proposed to work as inhibitors of MBLs. Both might show inhibition due to their strong binding to the active site zinc ions in MBLs using a "sulfide/hydroxyl release" strategy. If active, these compounds would prevent the enzymes from hydrolyzing β-lactam antibiotic drugs.The synthesis of thioacids was attempted through two routes. The initial synthesis involved thio-lactam formation using Lawesson’s reagent, followed by thio-lactam ring opening under basic conditions. An alternative method that was attempted utilized β-lactam ring opening under basic conditions followed by thionation of the resulting carboxylic acid. However, the thionation step was challenging when attempted on the highly-functionalized intermediates in both synthetic routes. The synthesis of the dicarboxylic acids was overall successful in 5 steps from commercially available penicillin derived starting material. The successfully synthesized targets may provide a new type of MBL inhibitor. This research also broadened the substrate scope of β-lactam ring opening under basic conditions, which could provide access to other β-lactam-derived enzyme inhibitors in the future.

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