Multidrug Efflux Pumps and Their Inhibitors Characterized by Computational Modeling

  • Venkata Krishnan Ramaswamy
  • Pierpaolo Cacciotto
  • Giuliano Malloci
  • Paolo Ruggerone
  • Attilio V. VargiuEmail author


Antimicrobial resistance is a key public health concern of our era due to an ever-increasing number of drug-resistant pathogens, including several Gram-negative bacilli. The latter are endowed with a low permeable outer membrane and with numerous chromosomally encoded multidrug efflux pumps, which are not only ubiquitous but also polyspecific, thus recognizing a broad range of compounds. Efflux pumps are a major defense mechanism of these organisms against antimicrobials as they can significantly increase the levels of resistance by allowing time for the organisms to develop specific resistance mechanisms. One of the potential strategies to reinvigorate the efficacy of antimicrobials is by joint administration with efflux pump inhibitors, which either block the substrate binding and/or hinder any of the transport-dependent steps of the pumps. In this chapter, we provide an overview of multidrug resistance efflux pumps, their inhibition strategies, and the important findings from the various computational simulation studies reported to date with respect to the rational design of inhibitors and on deciphering their mechanism of action.


Antimicrobial resistance Efflux pump ABC MATE RND P-glycoprotein Efflux pump inhibitor Molecular dynamics Molecular docking 



The research leading to the results discussed here was partly conducted as part of the Translocation Consortium ( and has received support from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement no. 115525, resources that are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies in kind contribution.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Venkata Krishnan Ramaswamy
    • 1
  • Pierpaolo Cacciotto
    • 1
  • Giuliano Malloci
    • 1
  • Paolo Ruggerone
    • 1
  • Attilio V. Vargiu
    • 1
    Email author
  1. 1.Department of PhysicsUniversity of CagliariCagliariItaly

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