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Microorganisms use efflux pumps to regulate their internal environment by removing toxic substances including antimicrobial agents. Studies have supported drug efflux pumps (EP) as a participant in the emergence of resistance towards antimicrobial drugs. Of the EPs, the NorA remains the most studied druggable target. In this study, the shikimate pathway-derived phenolic acids were evaluated against NorA (PDB ID: 1PW4) in silico subsequent to in vitro evaluations. Of the 22 compounds evaluated, sinapic acid (-9.0 kcal/mol) and p-coumaric acid (-6.3 kcal/mol) had the best and most prominent affinity for NorA relative to the standard ciprofloxacin (-4.9 kcal/mol). A further probe into the structural stability, flexibility and compactness of the resulting NorA-phenolic acids complexes through molecular dynamic simulations over a 100-ns period revealed p-coumaric acid as the best inhibitor of NorA relative to the reference standard. In vitro results further complimented the findings of the in-silico modelling. The antimicrobial screening showed MIC values in the range 31.2 to 62.5 μg/ml against S. aureus, E. coli, and P. aeruginosa, and compounds were bactericidal. Studies further revealed a synergistic effect between the compounds and ciprofloxacin with MIC reductions 4 to 16 times against all three baemphasized textcterial cultures. Hence, molecular insights of receptor-ligand interactions and antimicrobial screening gained from the present investigation will provide a new vision for the development of potent NorA efflux pump inhibitors.emphasized text
