title: Computational modelling of efflux pumps and their inhibitors.
abstract: Antimicrobial resistance is based on the multifarious strategies that bacteria adopt to face antibiotic therapies, making it a key public health concern of our era. Among these strategies, efflux pumps (EPs) contribute significantly to increase the levels and profiles of resistance by expelling a broad range of unrelated compounds - buying time for the organisms to develop specific resistance. In Gram-negative bacteria, many of these chromosomally encoded transporters form multicomponent 'pumps' that span both inner and outer membranes and are driven energetically by a primary or secondary transporter component.One of the strategies to reinvigorate the efficacy of antimicrobials is by joint administration with EP inhibitors (EPI), which either block the substrate binding and/or hinder any of the transport-dependent steps of the pump. In this review, we provide an overview of multidrug-resistance EPs, their inhibition strategies and the relevant findings from the various computational simulation studies reported to date with respect to deciphering the mechanism of action of inhibitors with the purpose of improving their rational design.
authors.affiliation: Department of Physics, University of Cagliari, Monserrato, Cagliari, Italy.
authors.forename: Venkata Krishnan
authors.initials: VK
authors.lastname: Ramaswamy
authors.affiliation: Department of Physics, University of Cagliari, Monserrato, Cagliari, Italy.
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Cacciotto
authors.affiliation: Department of Physics, University of Cagliari, Monserrato, Cagliari, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Malloci
authors.affiliation: Department of Physics, University of Cagliari, Monserrato, Cagliari, Italy.
authors.forename: Attilio V
authors.initials: AV
authors.lastname: Vargiu
authors.affiliation: Department of Physics, University of Cagliari, Monserrato, Cagliari, Italy paolo.ruggerone@dsf.unica.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ruggerone
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003198:Computer Simulation; D024901:Drug Resistance, Multiple, Bacterial; D008958:Models, Molecular
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins
keywords: Bacteria; Computer simulations; Efflux systems; Molecular dynamics; Multidrug resistance