Targeting the two-component Agr system in Staphylococcus aureus: Molecular docking and dynamics insights into natural compound inhibition

The escalating prevalence of antimicrobial resistance, particularly in methicillin-resistant Staphylococcus aureus (MRSA), necessitates the development of alternative therapeutic strategies beyond traditional antibiotics. Targeting quorum sensing (QS), a bacterial communication mechanism that modulates virulence, biofilm development, and toxin secretion represents a promising anti-virulence approach. In S. aureus, the Accessory gene regulator (Agr) system, comprising the response regulator AgrA and the sensor kinase AgrC, plays a pivotal role in pathogenicity regulation. In this study, a structure-based computational workflow was employed to identify food-derived quorum sensing inhibitors (QSIs) targeting AgrA and AgrC. A curated set of bioactive compounds from the FooDB database was subjected to ADMET profiling, molecular docking, molecular dynamics (MD) simulations, and MM-PBSA binding free energy calculations. Several candidate compounds exhibited strong binding affinities (ranging from −9 to −7.5 kcal/mol) and stable interactions with key residues of AgrA and AgrC. MD simulations over 100 ns confirmed the stability of these protein–ligand complexes, while Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) analysis and interaction fingerprint analysis indicated favourable binding energetics. Collectively, these findings suggest that food-derived compounds hold significant potential as safe and effective QSIs capable of disrupting S. aureus virulence pathways. This anti-virulence strategy offers a novel and resistance-mitigating therapeutic avenue by attenuating bacterial pathogenicity without exerting direct bactericidal pressure.