Date of Award
Winter 12-15-2017
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
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.
Language
English (en)
Chair and Committee
Timothy A. Wencewicz
Committee Members
Kevin D. Moeller, John R. Bleeke, John-Stephen Taylor, Jeffrey P. Henderson,
Recommended Citation
Shapiro, Justin, "The Chemistry and Biology of Iron-Scavenging Natural Products from Pathogenic Acinetobacter baumannii" (2017). Arts & Sciences Electronic Theses and Dissertations. 1201.
https://openscholarship.wustl.edu/art_sci_etds/1201
Comments
Permanent URL: https://doi.org/10.7936/K7X066F6