Abstract
Antibiotics are facing significant challenges due to the emergence of resistance and the slow pace of discovery. A deeper understanding of the enzymes responsible for antibiotic resistance and virulence is important to address this growing threat. This dissertation focuses on investigating key enzymatic mechanisms underlying tetracycline resistance and tabtoxin biosynthesis. Specifically, a series of inhibitors, including two covalent inhibitors, were rationally designed and synthesized to target tetracycline destructases, with the goal of restoring the efficacy of tetracycline antibiotics through combination therapy. In parallel, the early steps of tabtoxin biosynthesis were explored. A SAM-dependent enzyme TblA was found to exhibit unexpected cyclopropane synthase activity, expanding the known catalytic repertoire of this enzyme family. These findings provide new insights into antibiotic resistance and biosynthetic enzymes, offering promising strategies for combating antibiotic resistance and expanding our knowledge of enzyme functions.
Committee Chair
Timothy Wencewicz
Committee Members
Gautam Dantas; John-Stephen Taylor; Joseph Jez; Kevin Moeller
Degree
Doctor of Philosophy (PhD)
Author's Department
Chemistry
Document Type
Dissertation
Date of Award
8-4-2025
Language
English (en)
DOI
https://doi.org/10.7936/sgh7-vq90
Recommended Citation
Li, Ruihao, "Molecular Mechanisms of Enzymes Driving Antibiotic Resistance and Virulence" (2025). Arts & Sciences Theses and Dissertations. 3601.
The definitive version is available at https://doi.org/10.7936/sgh7-vq90