Iron is an essential growth element, but the availability of iron in an oxidizing environment is severely limited by the insolubility of Fe(OH)3. Microbes respond to this limitation by synthesizing low-molecular-weight chelating agents, siderophores, for which there are membrane-bound receptors. Often bacteria synthesize several siderophores and/or express multiple receptors. There is a clear link between iron and microbial virulence. Pathogenicity increases of up to 107 have been observed when the bacteriostatic effects of human iron complexing proteins are overcome. Previous studies have focussed on the structures of siderophores and the relationship of stereochemistry to siderophore mediated iron transport. Future work will address the dynamics of siderophore complexation in addition to the identification of new siderophores and their structure/function relationships. Fluorescent probes will be attached to siderophores to monitor both the spatial and temporal uptake of iron mediated by siderophores. The kinetics of ligand exchange and complex isomerization in catechol siderophores will be studied by NMR, and competition experiments will be used to obtain full thermodynamic characterization of siderophores. The overall focus of this research continues to be the coordination chemistry of siderophores, the connection of this chemistry to their biological activity, and the consequent medical significance of the results.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI011744-24
Application #
2671669
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1976-04-01
Project End
1999-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
24
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Wyckoff, Elizabeth E; Allred, Benjamin E; Raymond, Kenneth N et al. (2015) Catechol Siderophore Transport by Vibrio cholerae. J Bacteriol 197:2840-9
Fukushima, Tatsuya; Allred, Benjamin E; Raymond, Kenneth N (2014) Direct evidence of iron uptake by the Gram-positive siderophore-shuttle mechanism without iron reduction. ACS Chem Biol 9:2092-100
Naikare, Hemant; Butcher, James; Flint, Annika et al. (2013) Campylobacter jejuni ferric-enterobactin receptor CfrA is TonB3 dependent and mediates iron acquisition from structurally different catechol siderophores. Metallomics 5:988-96
Sia, Allyson K; Allred, Benjamin E; Raymond, Kenneth N (2013) Siderocalins: Siderophore binding proteins evolved for primary pathogen host defense. Curr Opin Chem Biol 17:150-7
Allred, Benjamin E; Correnti, Colin; Clifton, Matthew C et al. (2013) Siderocalin outwits the coordination chemistry of vibriobactin, a siderophore of Vibrio cholerae. ACS Chem Biol 8:1882-7
Fukushima, Tatsuya; Allred, Benjamin E; Sia, Allyson K et al. (2013) Gram-positive siderophore-shuttle with iron-exchange from Fe-siderophore to apo-siderophore by Bacillus cereus YxeB. Proc Natl Acad Sci U S A 110:13821-6
Fukushima, Tatsuya; Sia, Allyson K; Allred, Benjamin E et al. (2012) Bacillus cereus iron uptake protein fishes out an unstable ferric citrate trimer. Proc Natl Acad Sci U S A 109:16829-34
Correnti, Colin; Richardson, Vera; Sia, Allyson K et al. (2012) Siderocalin/Lcn2/NGAL/24p3 does not drive apoptosis through gentisic acid mediated iron withdrawal in hematopoietic cell lines. PLoS One 7:e43696
Correnti, Colin; Clifton, Matthew C; Abergel, Rebecca J et al. (2011) Galline Ex-FABP is an antibacterial siderocalin and a lysophosphatidic acid sensor functioning through dual ligand specificities. Structure 19:1796-806
Hoette, Trisha M; Clifton, Matthew C; Zawadzka, Anna M et al. (2011) Immune interference in Mycobacterium tuberculosis intracellular iron acquisition through siderocalin recognition of carboxymycobactins. ACS Chem Biol 6:1327-31

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