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. Un...

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Autores principales:	Cesar A. López, Timothy Travers, Klaas M. Pos, Helen I. Zgurskaya, S. Gnanakaran
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cf62dd8e3374478284349c2fc6b3abe6
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spelling	oai:doaj.org-article:cf62dd8e3374478284349c2fc6b3abe62021-12-02T15:04:56ZDynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface10.1038/s41598-017-16497-w2045-2322https://doaj.org/article/cf62dd8e3374478284349c2fc6b3abe62017-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-16497-whttps://doaj.org/toc/2045-2322Abstract 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.Cesar A. LópezTimothy TraversKlaas M. PosHelen I. ZgurskayaS. GnanakaranNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cesar A. López Timothy Travers Klaas M. Pos Helen I. Zgurskaya S. Gnanakaran Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface
description	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.
format	article
author	Cesar A. López Timothy Travers Klaas M. Pos Helen I. Zgurskaya S. Gnanakaran
author_facet	Cesar A. López Timothy Travers Klaas M. Pos Helen I. Zgurskaya S. Gnanakaran
author_sort	Cesar A. López
title	Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface
title_short	Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface
title_full	Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface
title_fullStr	Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface
title_full_unstemmed	Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface
title_sort	dynamics of intact mexab-oprm efflux pump: focusing on the mexa-oprm interface
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/cf62dd8e3374478284349c2fc6b3abe6
work_keys_str_mv	AT cesaralopez dynamicsofintactmexaboprmeffluxpumpfocusingonthemexaoprminterface AT timothytravers dynamicsofintactmexaboprmeffluxpumpfocusingonthemexaoprminterface AT klaasmpos dynamicsofintactmexaboprmeffluxpumpfocusingonthemexaoprminterface AT helenizgurskaya dynamicsofintactmexaboprmeffluxpumpfocusingonthemexaoprminterface AT sgnanakaran dynamicsofintactmexaboprmeffluxpumpfocusingonthemexaoprminterface
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Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface

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