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Title: Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface

Abstract

Antibiotic efflux is one of the most critical mechanisms leading to bacterial multidrug resistance. Antibiotics are effluxed out of the bacterial cell by a tripartite efflux pump, a complex machinery comprised of outer membrane, periplasmic adaptor, and inner membrane protein components. Understanding the mechanism of efflux pump assembly and its dynamics could facilitate discovery of novel approaches to counteract antibiotic resistance in bacteria. We built here an intact atomistic model of the Pseudomonas aeruginosa MexAB-OprM pump in a Gram-negative membrane model that contained both inner and outer membranes separated by a periplasmic space. All-atom molecular dynamics (MD) simulations confirm that the fully assembled pump is stable in the microsecond timescale. Using a combination of all-atom and coarse-grained MD simulations and sequence covariation analysis, we characterized the interface between MexA and OprM in the context of the entire efflux pump. These analyses suggest a plausible mechanism by which OprM is activated via opening of its periplasmic aperture through a concerted interaction with MexA.

Authors:
 [1];  [1];  [2];  [3];  [1]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Goethe Univ., Frankfurt (Germany). Inst. of Biochemistry. Cluster of Excellence Frankfurt
  3. Univ. of Oklahoma, Norman, OK (United States). Dept. of Chemistry and Biochemistry
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of Oklahoma, Norman, OK (United States); Goethe Univ., Frankfurt (Germany)
Sponsoring Org.:
USDOE; LANL Laboratory Directed Research and Development (LDRD) Program; Defense Threat Reduction Agency (DTRA) (United States); National Inst. of Health (NIH) (United States); German Research Foundation (DFG); Human Frontier Science Program (HFSP)
OSTI Identifier:
1440470
Report Number(s):
LA-UR-16-27246
Journal ID: ISSN 2045-2322
Grant/Contract Number:
AC52-06NA25396; HDTRA1-14-1-0019; AI052293; SFB807; EXC115; HFSP-RGP0034/2013
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Lopez, Cesar A., Travers, Timothy, Pos, Klaas M., Zgurskaya, Helen I., and Gnanakaran, S.. Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface. United States: N. p., 2017. Web. doi:10.1038/s41598-017-16497-w.
Lopez, Cesar A., Travers, Timothy, Pos, Klaas M., Zgurskaya, Helen I., & Gnanakaran, S.. Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface. United States. doi:10.1038/s41598-017-16497-w.
Lopez, Cesar A., Travers, Timothy, Pos, Klaas M., Zgurskaya, Helen I., and Gnanakaran, S.. Tue . "Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface". United States. doi:10.1038/s41598-017-16497-w. https://www.osti.gov/servlets/purl/1440470.
@article{osti_1440470,
title = {Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface},
author = {Lopez, Cesar A. and Travers, Timothy and Pos, Klaas M. and Zgurskaya, Helen I. and Gnanakaran, S.},
abstractNote = {Antibiotic efflux is one of the most critical mechanisms leading to bacterial multidrug resistance. Antibiotics are effluxed out of the bacterial cell by a tripartite efflux pump, a complex machinery comprised of outer membrane, periplasmic adaptor, and inner membrane protein components. Understanding the mechanism of efflux pump assembly and its dynamics could facilitate discovery of novel approaches to counteract antibiotic resistance in bacteria. We built here an intact atomistic model of the Pseudomonas aeruginosa MexAB-OprM pump in a Gram-negative membrane model that contained both inner and outer membranes separated by a periplasmic space. All-atom molecular dynamics (MD) simulations confirm that the fully assembled pump is stable in the microsecond timescale. Using a combination of all-atom and coarse-grained MD simulations and sequence covariation analysis, we characterized the interface between MexA and OprM in the context of the entire efflux pump. These analyses suggest a plausible mechanism by which OprM is activated via opening of its periplasmic aperture through a concerted interaction with MexA.},
doi = {10.1038/s41598-017-16497-w},
journal = {Scientific Reports},
number = ,
volume = 7,
place = {United States},
year = {Tue Nov 28 00:00:00 EST 2017},
month = {Tue Nov 28 00:00:00 EST 2017}
}

Journal Article:
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