In silico exploration of bioactive compounds targeting the CrtM to impede Staphylococcus aureus drug resistance: Pigment inhibitors.

Abstract

The World Health Organization has designated the Methicillin-resistant Staphylococcus aureus (MRSA) and its variants as high-priority threats owing to their enhanced virulence and pathogenic potential. Staphyloxanthin (STX), a prominent virulence factor of S. aureus, plays a dual role: it shields the bacterium from oxidative stress generated by the host immune response and preserves the cell membrane integrity. Dehydrosqualene synthase (CrtM), a prenyl transferase, is essential for catalyzing the first step of STX biosynthesis. In this study, we evaluated 144,000 compounds, including anticancer agents, inhibitors and approved drugs, and 3D bioactive molecules to inhibit the CrtM using computational approaches. Virtual screening was performed on the prepared compound library, followed by relative binding free energy calculations based on MM/GBSA for hit compounds and 100 ns molecular dynamics (MD) simulations for top 3 hit candidates. BPH-652, a known CrtM inhibitor, was used as the reference. Our results revealed that Cmpd1 and Cmpd2 exhibit docking scores of -13.113 kcal/mol and -13.015 kcal/mol, respectively compared to BPH-652(-10.74 kcal/mol) against the CrtM. The stability was further confirmed with relative binding free energies of -57.70 kcal/mol for BPH-652, and -104.74 and -113.20 kcal/mol for Cmpd1 and Cmpd2, respectively. MD simulations demonstrated stable behavior of Cmpd1 and Cmpd2 inside active site of CrtM with minimal fluctuations, the binding energy calculated from MD trajectories also support strong affinity of these compounds. Their favorable ADME properties suggest the potential for further validation in in vitro and in vivo levels.