Complex between S. aureus hemophore and human hemoglobin as a target for novel antimicrobial agents: from complex characterization to compounds identification

The Isd (Iron-regulated Surface Determinant) system of Staphylococcus aureus, together with siderophores, provides iron to sustain bacterial metabolism during colonization of the host. The system is composed of eight proteins that extract heme from hemoglobin (Hb), transfer it through the bacterial cell wall and membrane, and degrade the cofactor to retrieve iron. The project focuses on the complex between human Hb and IsdB, the cell-wall anchored protein in charge of binding Hb and remove heme. An isofunctional protein, IsdH, is also localized on the cell surface, but in vivo studies report that S. aureus relies especially on IsdB to infect the human host. This experimental evidence and the MRSA threat make IsdB a suitable target to develop new antimicrobial agents. Interference with protein-protein interactions poses new opportunities and challenges for the development of innovative therapeutics and requires an in-depth knowledge of biochemical details of protein complexes. The main aims of my Ph.D. project were the biochemical and biophysical characterization of IsdB-Hb interaction and heme extraction, and the validation of molecules identified by in silico screening as potential disruptors of the complex (in collaboration with Prof.ssa F. Spyrakis, Università di Torino). These protein-protein interaction inhibitors might in principle find application as first-in-class antimicrobials, cutting down the iron supply.