Abstract

In canonical β-Lactam antibiotics, such as penicillin, the strained nature of the β-Lactam ring leads to acylation of the catalytic serine in the active site of transpeptidases. In 2018, our lab reported a novel mechanism for monocyclic β-lactam antibiotics in the inhibition of glutamine synthetase (GS) by a natural product, tabtoxinine-β-lactam (TβL) using a 3-hydroxy-β-lactam pharmacophore. This work aims to generalize the β-lactam scaffold from TβL to act as a warhead against ATP-dependent carboxylate-amine ligase enzymes, with dihydrofolate synthetase (DHFS) as the test case. A pure 3-hydroxy-β-lactam warhead was synthesized and ligated both chemically and chemoenzymatically to different pteridine mimics. These molecules were tested against DHFS biochemical activity and a novel 3-hydroxy-β-lactam inhibitor of DHFS was discovered. These findings represent a significant expansion of the role that β-lactam antibiotics play against the bacterial proteome.

Committee Chair

Timothy A. Wencewicz

Committee Members

Jonathan C. Barnes, Kevin D. Moeller, Jay W. Ponder, Christina L. Stallings,

Degree

Doctor of Philosophy (PhD)

Author's Department

Chemistry

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

Winter 12-15-2022

Language

English (en)

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