Computational Study Reveals the Molecular Mechanism of the Interaction between the Efflux Inhibitor PAβN and the AdeB Transporter from Acinetobacter baumannii

[Image: see text] Phenylalanine-arginine β-naphthylamide (PAβN) is a broad-spectrum efflux pump inhibitor that has shown to potentiate the activity of antibiotics in Gram-negative bacteria. AdeB is a part of the AdeABC tripartite pump that plays a pivotal role in conferring efflux-mediated resistance in Acinetobacter baumannii. To understand the molecular mechanism of efflux pump inhibition by PAβN, we investigated the interaction of PAβN with AdeB using different computational methods. We observed that PAβN does not have specific binding interactions with the proximal binding site and interacts strongly with the distal binding pocket. The Phe loop located between the proximal and distal binding pockets plays a key role in the PAβN-mediated inhibition and acts as a gate between the binding pockets. Molecular dynamics simulations suggested that PAβN behaved like a climber as we observed switching of the interaction energies between the ligand and the key Phe residues of the binding site during the course of the simulation. PAβN uses the hydrophobic microenvironment formed by Phe residues in the distal binding pocket to keep the binding monomer in the binding conformation. The simulation data suggests that this binding event should result in the inhibition of the peristaltic mechanism and prevent the exporter from extruding any other substrates leading to the inhibition of the tripartite pump.