Date of Award
Doctor of Philosophy (PhD)
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.
Chair and Committee
Timothy A. Wencewicz
Jonathan C. Barnes, Kevin D. Moeller, Jay W. Ponder, Christina L. Stallings,
Virgin-Downey, Brett Wesley, "Non-Canonical Beta-Lactam Antibiotics" (2022). Arts & Sciences Electronic Theses and Dissertations. 2814.
Available for download on Sunday, December 21, 2025