Computational Discovery of Bioactive Compounds Targeting Conserved MSCRAMMs Adhesion Proteins to Disrupt...

Colonization by Staphylococcus aureus is a key event preceding invasive infections. During host interaction, the bacterium expresses Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs), a family of surface-associated adhesins that mediate attachment to extracellular matrix components and promote persistence. Targeting conserved MSCRAMM proteins may provide a preventive strategy to limit bacterial establishment.

A total of 249,079 bioactive compounds were compiled from the published literature and public databases. Following screening for drug-likeness and pharmacokinetic properties, 1,600 compounds were shortlisted. Core-genome analysis of MSCRAMM proteins was conducted using panX to identify conserved targets. Druggability and safety profiling were performed using the Target-Pathogen database and sequence similarity analysis against the human proteome to minimize off-target effects. Selected compounds were subjected to molecular docking, inhibition constant estimation, and molecular dynamics simulations to evaluate binding affinity and complex stability.

Among the 24 MSCRAMM proteins identified, six conserved proteins were prioritized as potential therapeutic targets. All demonstrated favorable druggability characteristics and minimal similarity to human proteins. Docking analysis revealed 18 compounds with strong binding affinities, of which 12 were non-hepatotoxic and exhibited stable interactions with multiple targets. Molecular dynamics simulations confirmed the structural integrity and sustained binding of the selected protein-ligand complexes.

These findings highlight the potential of targeting conserved MSCRAMM proteins as an anti-virulence approach and provide a basis for the future development of alternative strategies against antibiotic-resistant S. aureus.

The identified compounds represent promising candidates for further experimental validation aimed at preventing S. aureus colonization.