Sodium-Proton antiporter, NhaA is a ubiquitous protein found in cytoplasmic membranes of all the prokaryotic and eukaryotic systems. These antiporters have been widely studied in and their homologs, observed in humans, are found to be crucial for various pathophysiological conditions, such as hypertension, cardiac diseases, blood pressure fluctuation etc. NhaA is responsible for the virulent properties of many pathogens like , etc. In the present work, we have exploited in silico approaches to find lead phytomolecules that have the efficacy to interfere with the activities of sodium-proton antiporters in A database of the plant-based natural bioactive compounds was used to screen 350 phytochemicals from various plant sources as potential ligands for the Ec-NhaA protein (PDB ID: 4ATV). Further interactions between Ec-NhaA and ligands were analyzed by AutoDock Vina and proposed 46 ligands with a significant affinity for NhaA where the binding energy range from -7.5 to -9.3 kcal/mol. Physiochemical characterization suggested 26 ligands with non-BBB permeability, good GI absorption and solubility. As a final step, MD simulation for more than 100 ns duration suggested Luteolin, Apigenin and Rhamnocitrin with the best affinity and showing potential stable interaction with the target protein. This study proposed the potential compounds of natural origin as an interfering agent against sodium-proton transport activity that may lead to affect the survival of various pathogenic bacteria.Communicated by Ramaswamy H. Sarma.