Natural Products as MexB‐specific Efflux Pump Inhibitors Against Pseudomonas aeruginosa

Abstract

Antimicrobial resistance (AMR) remains a critical global health challenge, with the RND‐type MexAB–OprM efflux system of Pseudomonas aeruginosa playing a central role in intrinsic multidrug resistance (MDR) through the active extrusion of diverse antibiotics. In this study, we screened natural product libraries to identify safer alternatives capable of directly targeting MexB using computational approaches. A multi‐stage in silico pipeline was applied, involving virtual screening of 4687 plant‐derived compounds, followed by molecular docking against MexB, 100‐ns molecular dynamics simulations, MM‐PBSA binding free energy calculations, and ADMET profiling using SwissADME. Salvianolic acid A emerged as the top candidate, showing exceptional stability within the MexB binding pocket with low root‐mean square deviation (RMSD) values (∼1.8 Å for protein and < 1.8 Å for ligand), matching the stability of the reference inhibitor Phe‐Arg β ‐naphthylamide (PA β N) while exhibiting the most favorable binding free energy of all compounds tested (Δ G _bind = −68.9 kcal/mol) and a favorable predicted drug‐likeness profile. In contrast, forsythoside A and mirificin showed weaker stability and less favorable energetics. Overall, salvianolic acid A is identified as a promising, stable, and structurally validated natural lead compound for MexB inhibition, offering a strong computational basis for future experimental validation and development of novel EPIs to combat AMR in P. aeruginosa .