Date of Award
Doctor of Philosophy (PhD)
Antibiotic resistance is an increasing threat in today’s society. In order to overcome resistant bacteria, it is necessary to discover new drugs with novel mechanisms of action. This work focuses on the sideromycin pathway, encompassing the biosynthetic production, mechanism of entry and hydrolysis-mediated drug release. Sideromycins are an interesting approach to combat the rise of antibiotic resistance since they provide a different avenue that overcomes problems that arise when entering the cell. The dissertation is separated into distinct sections dealing with the various areas of interest in the sideromycin pathway, particularly for the sideromycin, salmycin, produced by Streptomyces violaceus. The first two sections encompass the mechanism of entry through the siderophore transport protein, FhuD2, in Staphylococcus aureus. We report a novel siderophore purification method that utilizes the displacement mechanism of FhuD2. In another section, we discuss the biosynthesis of trihydroxamate siderophores, revealing evidence for secondary gene clusters responsible for the diversity of siderophores that originate from naturally produced ferrioxamine-E. We also present in another section insights into the hydrolysis-mediated drug release mechanism, providing evidence of a relationship between iron-reduction/release, and hydrolysis of the drug.
Chair and Committee
Timothy A. Wencewicz
John-Stephen Taylor, Kevin D. Moeller, Jeffrey P. Henderson, Meredith Jackrel,
Rivera, Gerry Sann Macaraeg, "Sideromycin Pathway Elucidation: Insights into Salmycin Biosynthesis, Transport Paradigms, and Drug Release" (2019). Arts & Sciences Electronic Theses and Dissertations. 2014.