Synergistic Effect of Potentilla nepalensis with Antibiotics: Targeting Bacterial Efflux Pumps Through Pharmacological, and Computational Approaches.

Abstract

Potentilla nepalensis (Family: Rosaceae) has been traditionally used to treat burns, gastrointestinal disorders, headaches, dysentery, colds, and skin diseases. This study investigates the synergistic antibacterial interactions between methanolic extracts of P. nepalensis roots and shoots with selected antibiotics, supported by molecular docking and molecular dynamics (MD) simulations to elucidate the underlying mechanisms. Phytochemical profiling revealed comparable constituents in root and shoot extracts, with high-performance liquid chromatography (HPLC) quantification highlighting significant variations in key bioactive compounds. Synergistic antibacterial interactions were evaluated using combinations of roots and shoot extracts with ampicillin and chloramphenicol against S. aureus and E. coli. These combinations demonstrated significant bioactivity enhancements ranging from 5-32.26 folds with ampicillin and 8-62.5 folds with chloramphenicol. Molecular docking revealed strong binding of ellagic acid to the NorA efflux pump (PDB ID: 7LO8) and multidrug transporter protein, AcrB (PDB ID: 4DX5). MD simulations further confirmed the stability of these protein-ligand complexes, supported by MM-GBSA analysis. Pharmacokinetic evaluations indicated poor solubility and low permeability of ellagic acid leading to primary fecal elimination. However, its favorable safety profile and minimal drug-drug interaction suggest its potential as a safe therapeutic agent. The findings underscore the potential of P. nepalensis as an adjuvant in antibiotic therapy, offering a promising strategy to combating drug-resistant bacterial infections. Further in vivo studies and clinical evaluations are warranted to confirm its therapeutic efficacy.