Synergistic and multi-targeting efficacy of Acalypha wilkesiana and Mirabilis jalapa: an integrated in-vitro and in-silico investigation against Staphylococcus aureus and Pseudomonas aeruginosa

The escalating prevalence of multidrug-resistant skin pathogens specifically methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa demands therapeutic strategies that move beyond conventional single-target antibiotics. This study investigates the antimicrobial, synergistic, and molecular mechanisms of Acalypha wilkesiana and Mirabilis jalapa, two plants used in West African ethnopharmacology for wound management. Ethanol and aqueous leaf extracts were prepared and purified via silica gel column chromatography using a gradient n-hexane: ethyl acetate system. Antimicrobial efficacy was quantified by Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) assays. Synergism was evaluated by the checkerboard method (Fractional Inhibitory Concentration Index). Membrane integrity was probed by K⁺ and protein leakage assays. Constituent phytochemicals; Quercetin and Chlorogenic Acid were docked against S. aureus Peptide Deformylase (PDF; PDB: 1Q1Y) and P. aeruginosa LasR (PDB: 2UV0), followed by 50-ns Molecular Dynamics (MD) simulations and MM-GBSA binding free energy calculations. Ethanol extracts of A. wilkesiana demonstrated potent activity (MIC: 12.5 mg/ml against P. aeruginosa ATCC 10145). Combination with M. jalapa yielded strong synergy (FIC index ≤ 0.25–0.50). Membrane leakage assays revealed catastrophic membrane failure: K⁺ leakage, 15.86 Cmol/kg; protein efflux, 3.83 Cmol/kg. Quercetin exhibited high-affinity inhibition of S. aureus PDF (docking score: − 9.802 kcal/mol; MM-GBSA ΔGbind: − 58.42 kcal/mol; RMSD: 1.45 ± 0.2 Å), with critical H-bonds at Gly49/Gln50 maintained for 88% of simulation frames. Chlorogenic Acid bound the LasR autoinducer pocket (docking score: − 9.7 kcal/mol; MM-GBSA: − 48.15 kcal/mol; RMSD: 1.80 ± 0.3 Å), with hydrophobic contacts at Trp60 persisting for 95% of the trajectory. Quercetin and Chlorogenic Acid suppress bacterial protein maturation (PDF) and quorum-sensing (LasR), while saponins and terpenes execute catastrophic membrane disruption. This synergistic multi-target strategy establishes Quercetin and Chlorogenic Acid as viable scaffolds for anti-virulence drug development against resistant skin pathogens.