Date of Award
Winter 12-15-2021
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
As the number of multi-drug resistant bacterial infections continue to rise, the development of new antibiotics has fallen, leading to a disproportionate number of infections to tools necessary to combat them. As a result, new therapeutic strategies, treatments, and targets need to be investigated. One such strategy includes the exploitation of bacterial nutrient acquisition pathways as a means to either shuttle active compounds across the cellular envelope or disrupt vital nutrients from entering the cell. In order to properly utilize this strategy, basic research must investigate these pathways and determine appropriate targets. Pathogenic bacteria produce and secrete small molecule iron chelators, termed siderophores, to import vital ferric iron during infection. Herein, we outline several biological activity-guided synthetic approaches employed to study both the biosynthesis and mechanism of common hydroxamate and catecholate siderophores utilized by pathogenic bacteria. Furthering the current understanding of the biosynthesis of the natural siderophore class, the desferrioxamines, we synthesized rationally designed inhibitors and probes based on the previously proposed mechanism of biosynthesis. With our collaborators at the University at Buffalo, we were able to solve several x-ray crystal structures of the NIS Synthetase, DesD, in various functional and inhibited states. We synthesized a 5'-O-sulfamoyl adenosine (AMS) compound that mimics the DesD acyl adenylate intermediate. This is the first example of an AMS type inhibitor bound to a NIS Synthetase. We completed full biochemical characterization of the AMS inhibitor which revealed selective inhibition of the DesD macrolactamization step. With this knowledge in hand, we designed and synthesized additional biochemical probes related to desferrioxamine biosynthetic shunt products to further account for the diversity of structures of the members of the desferrioxamines. These chemical tools and the resulting biochemical analyses allowed us to propose a new unified mechanism for desferrioxamine biosynthesis. Further, we developed a variety of synthetic routes to catecholate and phenolate-oxazoline siderophores that inhibit siderophore utilization in the human pathogen Acinetobacter baumannii and represent promising new therapeutic leads.
Language
English (en)
Chair and Committee
John-Stephen Taylor
Committee Members
Vladimir B. Birman, Jeffrey P. Henderson, Andrew M. Gulick
Recommended Citation
Banas, Victoria Suzanne, "Siderophore-Based Therapeutics and Chemical Probes" (2021). Arts & Sciences Electronic Theses and Dissertations. 2566.
https://openscholarship.wustl.edu/art_sci_etds/2566