Structural Basis for Xenosiderophore Utilization by the Human Pathogen Staphylococcus aureus
| Autor: | Timothy A. Wencewicz, Nathaniel P. Endicott, Eries Lee |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Methicillin-Resistant Staphylococcus aureus Models Molecular Siderophore Iron Static Electricity Gene Expression Siderophores Human pathogen ATP-binding cassette transporter Biology Deferoxamine 010402 general chemistry medicine.disease_cause 01 natural sciences Binding Competitive Microbiology 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Cations Extracellular medicine Quenching (fluorescence) Membrane Transport Proteins Sideromycin 0104 chemical sciences Kinetics 030104 developmental biology Infectious Diseases Biochemistry chemistry Staphylococcus aureus Periplasmic Binding Proteins medicine.drug Protein Binding |
| Zdroj: | ACS infectious diseases. 3(7) |
| ISSN: | 2373-8227 |
| Popis: | Staphylococcus aureus produces a cocktail of metallophores (staphylopine, staphyloferrin A, and staphyloferrin B) to scavenge transition metals during infection of a host. In addition, S. aureus displays the extracellular surface lipoproteins FhuD1 and FhuD2 along with the ABC transporter complex FhuCBG to facilitate the use of hydroxamate xenosiderophores such as desferrioxamine B (DFOB) for iron acquisition. DFOB is used as a chelation therapy to treat human iron overload diseases and has been linked to an increased risk of S. aureus infections. We used a panel of synthetic DFOB analogs and a FhuD2-selective trihydroxamate sideromycin to probe xenosiderophore utilization in S. aureus and establish structure-activity relationships for Fe(III) binding, FhuD2 binding, S. aureus growth promotion, and competition for S. aureus cell entry. Fe(III) binding assays and FhuD2 intrinsic fluorescence quenching experiments revealed that diverse chemical modifications of the terminal ends of linear ferrioxamine siderophores influences Fe(III) affinity but not FhuD2 binding. Siderophore-sideromycin competition assays and xenosiderophore growth promotion assays revealed that S. aureus SG511 and ATCC 11632 can distinguish between competing siderophores based exclusively on net charge of the siderophore-Fe(III) complex. Our work provides a roadmap for tuning hydroxamate xenosiderophore scaffolds to suppress (net negative charge) or enhance (net positive or neutral charge) uptake by S. aureus for applications in metal chelation therapy and siderophore-mediated antibiotic delivery, respectively. |
| Databáze: | OpenAIRE |
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