Targeting AgrA in <i>Staphylococcus aureus</i> : An in Silico Approach for Identifying Antipathogenic Compounds

ABSTRACT Staphylococcus aureus is an emerging nosocomial pathogen with a surge in multidrug resistance, rendering conventional antibiotic treatments futile. This underscores the necessity of alternative therapeutic strategies. Targeting the quorum‐sensing system in S. aureus could be a viable alternative, as quorum‐sensing inhibitors attenuate pathogenicity without imposing selective pressure on survival. AgrA, the response regulator of the Agr QS system, plays a pivotal role in regulating the expression of virulence‐associated genes and represents a promising molecular target for antivirulence therapy. In this study, 1281 compounds retrieved from the IMPPAT database were screened to identify AgrA inhibitors using in silico approaches. ADME screening and molecular docking identified Triptriolide and triptonide as top hits with effective binding scores of −7.8 kcal/mol and −7.7 kcal/mol, respectively. Molecular dynamics simulation revealed improved stability of Triptriolide complex as evidenced by RMSD, RMSF, Rg, SASA, and Hbond values. Principal component analysis (PCA) and Free Energy Landscape (FEL) analysis confirmed the structural stability of the complex. These findings suggest that Triptriolide may interact with AgrA, and potentially impair its DNA‐binding ability, thereby suppressing the virulence. However, further experimental validation is essential to establish Triptriolide as a potent antivirulence drug in the management of S. aureus infections.