ERASE investigates two mechanisms of iron acquisition, heme scavenging by IsdB/IsdH and siderophore biosynthesis catalyzed by SbnA, and aims to target them for the development of innovative antimicrobials likely able to elude the common mechanisms of resistance exploited by bacteria.
The project pursues the following objectives:
1. Provide the necessary biochemical and biophysical knowledge on IsdB/IsdH and their interaction with Hb, and on SbnA, to support the development of inhibitors of iron supply in S. aureus.
2. Develop small molecules that interfere with the IsdB/IsdH-mediated iron acquisition from Hb. The small molecules will be identified in silico by their ability to bind to a pocket on the Hb surface that is involved in IsdB/IsdH recognition.
3. Develop small molecule inhibitors of the SbnA enzyme.
4. Validate the molecules identified in silico using ad hoc developed biochemical, biophysical and microbiological assays.
We expect to gain a deep functional and structural knowledge of the systems under investigation, paving the way for the effective identification of inhibitors of IsdB/IsdH-Hb interaction and of SbnA. Molecules will undergo cycles of identification/validation/optimization thanks to the synergy of the participant expertise.
The final expected result and deliverable of the project is the optimization, and full characterization, of 1-2 molecules for each of the two targets able to significantly impair S. aureus iron uptake, and hence inhibit its growth (growth reduction 50% compared to the untreated control). The compounds will represent a revolutionary resource to fight MRSA-induced infections.