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Publication Abstract from PubMed

Staphylococcus aureus is a human pathogen causing globally significant morbidity and mortality. The development of antibiotic resistance in S. aureus highlights the need for a preventive vaccine. Here we explore the structure and function of FhuD2, a staphylococcal surface lipoprotein mediating iron-uptake during invasive infection, recently described as a promising vaccine candidate. Differential scanning fluorimetry and calorimetry studies revealed that FhuD2 is stabilized by hydroxamate siderophores. The FhuD2-ferrichrome interaction was of nanomolar affinity in surface plasmon resonance experiments and fully Fe3+-dependent. We determined the x-ray crystallographic structure of ligand-bound FhuD2 at 1.9A resolution, revealing the bilobate fold of class III solute-binding proteins (SBPs). The ligand, ferrichrome, occupies a cleft between the FhuD2 N- and C-terminal lobes. Many FhuD2-siderophore interactions enable the specific recognition of ferrichrome. Biochemical data suggest that FhuD2 does not undergo significant conformational changes upon siderophore binding, supporting the hypothesis that the ligand-bound complex is essential for receptor engagement and uptake. Finally, immunizations with FhuD2 alone or FhuD2 formulated with hydroxamate siderophores were equally protective in a murine staphylococcal infection model, confirming the suitability and efficacy of apo-FhuD2 as a protective antigen, and suggesting that other Class III SBPs might also be exploited as vaccine candidates.

Structural and functional characterization of the Staphylococcus aureus virulence factor and vaccine candidate FhuD2.,Mariotti P, Malito E, Biancucci M, Lo Surdo P, Mishra RP, Nardi-Dei V, Savino S, Nissum M, Spraggon G, Grandi G, Bagnoli F, Bottomley MJ Biochem J. 2012 Oct 31. PMID:23113737^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.