Structure based discovery of small molecule suppressors targeting bacterial lysozyme inhibitors

► PliC/MliC are bacterial proteins inhibiting lysozyme activity. ► Agents inhibiting this protein–protein interaction are promising novel antibiotics. ► A homology model of the Salmonella lysozyme inhibitor complex was created. ► Virtual screening using the homology model identified 28 interesting molecules. ► In vitro testing validated four molecules as first inhibitors of this interaction. The production of lysozyme inhibitors, competitively binding to the lysozyme active site, is a bacterial strategy to prevent the lytic activity of host lysozymes. Therefore, suppression of the lysozyme–inhibitor interaction is an interesting new approach for drug development since restoration of the bacterial lysozyme sensitivity will support bacterial clearance from the infected sites. Using molecular modelling techniques the interaction of the Salmonella PliC inhibitor with c-type lysozyme was studied and a protein–protein interaction based pharmacophore model was created. This model was used as a query to identify molecules, with potential affinity for the target, and subsequently, these molecules were filtered using molecular docking. The retained molecules were validated as suppressors of lysozyme inhibitory proteins using in vitro experiments revealing four active molecules.