Abstract

Multidrug resistant (MDR) Gram-negative bacteria represent a global health crisis. Traditional antibiotics create selective pressure and breed resistance, making our current drugs less and less effective. Targeting of bacterial virulence factors has gained interest as an alternative strategy to potentially circumvent this problem. Virulent Acinetobacter baumannii synthesize and secrete pre-acinetobactin, a small molecule metal chelator that scavenges life-sustaining iron and is critical for establishing infection. The work described herein sheds light on the unusual properties of a non-enzymatic isomerization from pre-acinetobactin to acinetobactin and proposes a siderophore-swapping mechanism by which A. baumannii expands its pH window for virulence. Knowledge from structure-activity studies of the natural siderophores was used to design a rigidified pre-acinetobactin analog with antibiotic activity. Oxidation of the phenolate-oxazoline (pre-acinetobactin) to a phenolate-oxazole (oxidized pre-acinetobactin) confers low-micromolar MIC90 under iron deficient conditions against a panel of clinical MDR A. baumannii isolates. This work helps to lay a foundation for developing antivirulence agents to combat disease and resistance.

Committee Chair

Timothy A. Wencewicz

Committee Members

Kevin D. Moeller, John R. Bleeke, John-Stephen Taylor, Jeffrey P. Henderson,

Comments

Permanent URL: https://doi.org/10.7936/K7X066F6

Degree

Doctor of Philosophy (PhD)

Author's Department

Chemistry

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

Winter 12-15-2017

Language

English (en)

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Chemistry Commons

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