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

ACS Omega
Shirin JamshidiKhondaker Miraz Rahman

Abstract

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 i...Continue Reading

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Citations

Jun 1, 2019·FEMS Microbiology Reviews·Mark LawsKhondaker Miraz Rahman
May 14, 2019·Chembiochem : a European Journal of Chemical Biology·Lixin YangLihe Zhang
Feb 20, 2020·Future Microbiology·Abigail L ColcloughJessica Ma Blair
Feb 6, 2020·International Journal of Molecular Sciences·Alessio AtzoriPaolo Ruggerone
May 4, 2021·Current Opinion in Microbiology·Helen I ZgurskayaPaolo Ruggerone
Dec 28, 2021·Tissue Barriers·Pownraj BrindangnanamMohane Selvaraj Coumar

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Software Mentioned

Smina
AutoDock Vina
PBSA
Vina
OFFSET
Accelrys
Model webserver
Swiss
AutoDock Smina
GOLD

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