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Identification of small molecules affecting the interaction between human hemoglobin and Staphylococcus aureus IsdB hemophore
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Identification of small molecules affecting the interaction between human hemoglobin and Staphylococcus aureus IsdB hemophore
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Journal Article
Identification of small molecules affecting the interaction between human hemoglobin and Staphylococcus aureus IsdB hemophore
2024
Overview
Human hemoglobin (Hb) is the preferred iron source of
Staphylococcus aureus
. This pathogenic bacterium exploits a sophisticated protein machinery called Iron-regulated surface determinant (Isd) system to bind Hb, extract and internalize heme, and finally degrade it to complete iron acquisition. IsdB, the surface exposed Hb receptor, is a proven virulence factor of
S. aureus
and the inhibition of its interaction with Hb can be pursued as a strategy to develop new classes of antimicrobials. To identify small molecules able to disrupt IsdB:Hb protein–protein interactions (PPIs), we carried out a structure-based virtual screening campaign and developed an
ad hoc
immunoassay to screen the retrieved set of commercially available compounds. Saturation-transfer difference (STD) NMR was applied to verify specific interactions of a sub-set of molecules, chosen based on their efficacy in reducing the amount of Hb bound to IsdB. Among molecules for which direct binding was verified, the best hit was submitted to ITC analysis to measure the binding affinity to Hb, which was found to be in the low micromolar range. The results demonstrate the viability of the proposed in silico
/
in vitro experimental pipeline to discover and test IsdB:Hb PPI inhibitors. The identified lead compound will be the starting point for future SAR and molecule optimization campaigns.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
