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Front. Microbiol. | doi: 10.3389/fmicb.2018.01144

Molecular determinants of the promiscuity of MexB and MexY multidrug transporters of Pseudomonas aeruginosa

  • 1Physics, Università degli studi di Cagliari, Italy
  • 2Basilea Pharmaceutica (Switzerland), Switzerland

Secondary multidrug transporters of the Resistance-Nodulation-cell Division (RND) superfamily contribute crucially to antibiotic resistance in Gram-negative bacteria. Compared to the most studied transporter AcrB of Escherichia coli, little is known about the molecular determinants of distinct polyspecificities of the most important RND transporters MexB and MexY of Pseudomonas aeruginosa. In an effort to add knowledge on this topic, we performed an exhaustive atomic-level comparison of the main putative recognition sites (access and deep binding pockets) in these two Mex transporters. We identified an underlying link between some structural, chemical and dynamical features of the binding pockets and the physicochemical nature of the corresponding substrates recognized by either one or both pumps. In particular, mosaic-like lipophilic and electrostatic surfaces of the binding pockets provide for both proteins several multifunctional sites for diffuse binding of diverse substrates. Specific lipophilicity signatures of the weakly-conserved deep pocket suggest a key role of this site as a selectivity filter as in Acr transporters. Finally, the different dynamics of the bottom-loop in MexB and MexY support its possible role in binding of large substrates. Our work represents the first comparative study of the major RND transporters in P. aeruginosa and also the first structure-based study of MexY, for which no experimental structure is available yet.

Keywords: RND efflux pumps, multidrug transporters, Pseudomonas aeruginosa, antibiotic resistance, molecular dynamics, molecular modelling

Received: 16 Feb 2018; Accepted: 14 May 2018.

Edited by:

Vassiliy Bavro, University of Essex, United Kingdom

Reviewed by:

Martin Picard, UMR7099 Laboratoire de biologie physico chimique des protéines membranaires (LBPCPM), France
Jon W. Weeks, United States Food and Drug Administration, United States
JC Gumbart, Georgia Institute of Technology, United States  

Copyright: © 2018 Ramaswamy, Vargiu, Malloci, Dreier and Ruggerone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Paolo Ruggerone, Università degli studi di Cagliari, Physics, Cagliari, Italy,