Date of Award

Spring 5-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Chemistry

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The rise of antibiotic resistance is driving exploration of non-canonical antibiotic approaches, including neutralization of virulence factors. Multi-drug resistant (MDR) Gram-negative pathogens, including Acinetobacter baumannii, are of particular concern because of the small number of clinically useful antibiotics available for use. Here we both expand upon the existing knowledge of two of the siderophores of A. baumannii, acinetobactin and fimsbactin, and utilize this knowledge to synthesize novel compounds for the inhibition of pathogenic A. baumannii in whole cell assays.

Furthering the current knowledge of the natural siderophore systems of A. baumannii, we were able to investigate the interaction of acinetobactin with transport proteins, as well as examine the role of the fimsbactin siderophores in iron acquisition. Specifically, we report a crystal structure of siderophore binding protein BauB bound to holo-acinetobactin along with fluorscence quenching assays of acinetobactin and preacinetobactin analogs to BauB. Additionally, we isolate fimsbactin from A. baumannii and show the importance of balance between concentrations of siderophores. Further, we explore the cooperative relationship between siderophores fimsbactin A and fimsbactin F.

With this fundamental knowledge in hand, we report a new method for blocking iron acquisition in MDR A. baumannii as an antivirulence strategy using rigid oxazole analogs of the known siderophore pre-acinetobactin. In addition, we report the synthesis fimsbactin mimics and confirm utilization of siderophore uptake pathways in model A. baumannii systems. Moreover, the fully functional fimsbactin mimics possess a synthetic handle for the coupling of antibiotics allowing for simple incorporation into studies aimed at Trojan horse antibiotic delivery mechanisms.

Language

English (en)

Chair and Committee

Timothy Wencewicz

Committee Members

John-Stephen Taylor, Jonathan Barnes, Meredith Jackrel, Jeffrey Henderson,

Comments

Permanent URL: https://doi.org/10.7936/js96-7732

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