Date of Award
Winter 12-15-2022
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
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.
Language
English (en)
Chair and Committee
Timothy A. Wencewicz
Committee Members
Jonathan C. Barnes, Kevin D. Moeller, Jay W. Ponder, Christina L. Stallings,
Recommended Citation
Virgin-Downey, Brett Wesley, "Non-Canonical Beta-Lactam Antibiotics" (2022). Arts & Sciences Electronic Theses and Dissertations. 2814.
https://openscholarship.wustl.edu/art_sci_etds/2814