Screening the Pandemic Response Box identifies novel ligands of the Staphylococcus aureus protein arginine kinase, McsB.

BACKGROUND: The protein arginine kinase, McsB, plays a pivotal role in the stress-response mechanism of gram-positive bacteria and represents a potential target to combat gram-positive pathogens. There are currently no recorded ligands or inhibitors reported for bacterial McsB. METHODS AND RESULTS: We sought to identify novel ligands for the Staphylococcus aureus McsB by screening the Pandemic Response Box using thermal shift and cellular thermal shift assays. Six compounds were identified as McsB ligands, inducing positive shifts in the melting and aggregating temperature of the protein. Compounds MMV1593539 and MMV1782355 imparted the greatest stability to McsB across both assays. While none of the six McsB-targeting ligands yielded anti-bacterial effect against S. aureus under standard or heat stress conditions, MMV1634391, MMV1633968 and MMV1782213 effectively potentiated the activity of ciprofloxacin. Molecular docking and dynamic studies predict the ATP pocket of McsB as the likely binding site for MMV1593539 and MMV1782355. CONCLUSIONS: Compounds MMV1593539 and MMV1782355 stabilised McsB in two thermal stability assays while returning the most favourable docking scores and retaining protein-ligand stability in molecular dynamics. These ligands signify promising candidates for future drug discovery efforts aimed at inhibiting or exploiting the protein arginine kinase, McsB.