Microbial iron transport and mobilization is achieved using very powerful low-molecular-weight complexing agents which solubilize ferric ion through the formation of pseudo-octahedral complexes of high-spin Fe3+. These compounds, called siderophores, are manufactured by microorganisms specifically in response to their need for iron, an essential element for growth. The availability of iron to pathogens has been directly linked to the onset of disease in a number of illnesses associated with microbial infection. Transport of the iron occurs via several different mechanisms, as found either between different microorganisms or as parallel systems within one microorganism. We continue to use the replacement of kinetically labile Fe(III) by kinetically inert ions such as Cr(III) or Rh(III) in order to produce metal siderophore complexes of known and stable geometry to be used as biological probes of the transport process. Similarly, use of Ga(III) as a substitute for Fe(III) produces complexes of approximately the same thermodynamic stability and kinetic lability, but of dramatically different redox behavior. Thus Ga(III) substituted compounds can be used as specific probes for parts of the transport and uptake process which depend upon redox behavior. The synthesis of chelating agents which at least in part mimic particular siderophores can be designed so as to test for which parts of the siderophore are critical in the recognition process associated with microbial receptor proteins. Finally, the fundamental coordination chemistry and solution thermodynamic and ligand exchange behavior of the siderophores and their analogs will continue to be characterized as fundamental aspects of the biochemistry of this important class of compounds. In particular, the ligand exchange kinetics in non-aqueous media approximating the hydrophobic environment of the cell membrane will be examined for any significant difference from the aqueous ligand exchange behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI011744-16
Application #
3125022
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1976-04-01
Project End
1991-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
16
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
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
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
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; 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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