Staphylococcus aureus AgrA Modulators From South African Antimicrobial Plants

South African plants are an underutilized metabolite source for novel antimicrobials targeting key quorum sensing (QS) systems like the Staphylococcus aureus AgrA. AgrA-modulating metabolites constitute a new approach to reducing resistance development. This study created a library of 1211 metabolites from 266 South African plants with antimicrobial action. Metabolites' anti-QS activities were assessed using advanced computational methods. Molecular docking showed top five metabolites (hinokiflavone, asphodelin, elliptinone, mamegakinone, and robustaflavone). Most leads conformed to the Lipinski's rule of 5. Dynamics simulation revealed closest ∆G_bind for robustaflavone (-25.50 kcal/mol) and hinokiflavone (-20.94 kcal/mol) compared to the standard (-26.59 kcal/mol). Leads interacted with key residues (Asn62/201, Asp75/214, Arg94/233, and Asn95/234) and a high number of interactions that ensured thermodynamic stability and compactness. The identified leads could be key mechanistic contributors to the antimicrobial activity of their inherent plants. Both the plants and metabolites (robustaflavone and hinokiflavone) could be further explored following structural modification as QS inhibitors.