Abstract

Novel treatments for tuberculosis (TB) are urgently needed to conquer this global health crisis. Unlike canonical β-lactam antibiotics that target transpeptidases by hydrolyzing the lactam ring, tabtoxinine-β-lactam (TβL) functions as a potent glutamine synthetase (GS) inhibitor by forming a transition state mimic. TβL has the potential to be used as an anti-TB agent by targeting the nitrogen metabolic pathway of pathogenic mycobacteria. This work reported an innovative, convergent, and flexible cross-metathesis method to obtain the fully protected TβL scaffold. The trans-olefin intermediate provides possibilities for synthesizing various derivatives through alkene functionalization reactions. We also developed and optimized a solid phase peptide synthesis for peptide prodrug production and nine GS inhibitor peptide prodrugs were obtained to distinguish their inhibitory activities. Lastly, we investigated the TβL biosynthetic pathway, reconstituted three enzyme activities in vitro and determined the function of a novel C-methyltransferase, TblA. This work helped to lay a foundation for synthetic and biosynthetic pathways for TβL and other 3-hydroxy-β-lactam inhibitors of GS, which have the potential to be utilized as antimicrobial agents in the future.

Committee Chair

Timothy Wencewicz

Degree

Doctor of Philosophy (PhD)

Author's Department

Chemistry

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

1-17-2022

Language

English (en)

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Chemistry Commons

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