Cargando…

Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli

The drug/proton antiporter AcrB, engine of the major efflux pump AcrAB(Z)-TolC of Escherichia coli and other bacteria, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance (MDR) phenotype. Although hundreds of small molecules are kn...

Descripción completa

Detalles Bibliográficos
Autores principales: Atzori, Alessio, Malloci, Giuliano, Cardamone, Francesca, Bosin, Andrea, Vargiu, Attilio Vittorio, Ruggerone, Paolo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037162/
https://www.ncbi.nlm.nih.gov/pubmed/32013182
http://dx.doi.org/10.3390/ijms21030860
_version_ 1783500362615881728
author Atzori, Alessio
Malloci, Giuliano
Cardamone, Francesca
Bosin, Andrea
Vargiu, Attilio Vittorio
Ruggerone, Paolo
author_facet Atzori, Alessio
Malloci, Giuliano
Cardamone, Francesca
Bosin, Andrea
Vargiu, Attilio Vittorio
Ruggerone, Paolo
author_sort Atzori, Alessio
collection PubMed
description The drug/proton antiporter AcrB, engine of the major efflux pump AcrAB(Z)-TolC of Escherichia coli and other bacteria, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance (MDR) phenotype. Although hundreds of small molecules are known to be AcrB substrates, only a few co-crystal structures are available to date. Computational methods have been therefore intensively employed to provide structural and dynamical fingerprints related to transport and inhibition of AcrB. In this work, we performed a systematic computational investigation to study the interaction between representative carbapenem antibiotics and AcrB. We focused on the interaction of carbapenems with the so-called distal pocket, a region known for its importance in binding inhibitors and substrates of AcrB. Our findings reveal how the different physico-chemical nature of these antibiotics is reflected on their binding preference for AcrB. The molecular-level information provided here could help design new antibiotics less susceptible to the efflux mechanism.
format Online
Article
Text
id pubmed-7037162
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-70371622020-03-11 Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli Atzori, Alessio Malloci, Giuliano Cardamone, Francesca Bosin, Andrea Vargiu, Attilio Vittorio Ruggerone, Paolo Int J Mol Sci Article The drug/proton antiporter AcrB, engine of the major efflux pump AcrAB(Z)-TolC of Escherichia coli and other bacteria, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance (MDR) phenotype. Although hundreds of small molecules are known to be AcrB substrates, only a few co-crystal structures are available to date. Computational methods have been therefore intensively employed to provide structural and dynamical fingerprints related to transport and inhibition of AcrB. In this work, we performed a systematic computational investigation to study the interaction between representative carbapenem antibiotics and AcrB. We focused on the interaction of carbapenems with the so-called distal pocket, a region known for its importance in binding inhibitors and substrates of AcrB. Our findings reveal how the different physico-chemical nature of these antibiotics is reflected on their binding preference for AcrB. The molecular-level information provided here could help design new antibiotics less susceptible to the efflux mechanism. MDPI 2020-01-29 /pmc/articles/PMC7037162/ /pubmed/32013182 http://dx.doi.org/10.3390/ijms21030860 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Atzori, Alessio
Malloci, Giuliano
Cardamone, Francesca
Bosin, Andrea
Vargiu, Attilio Vittorio
Ruggerone, Paolo
Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli
title Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli
title_full Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli
title_fullStr Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli
title_full_unstemmed Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli
title_short Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli
title_sort molecular interactions of carbapenem antibiotics with the multidrug efflux transporter acrb of escherichia coli
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037162/
https://www.ncbi.nlm.nih.gov/pubmed/32013182
http://dx.doi.org/10.3390/ijms21030860
work_keys_str_mv AT atzorialessio molecularinteractionsofcarbapenemantibioticswiththemultidrugeffluxtransporteracrbofescherichiacoli
AT mallocigiuliano molecularinteractionsofcarbapenemantibioticswiththemultidrugeffluxtransporteracrbofescherichiacoli
AT cardamonefrancesca molecularinteractionsofcarbapenemantibioticswiththemultidrugeffluxtransporteracrbofescherichiacoli
AT bosinandrea molecularinteractionsofcarbapenemantibioticswiththemultidrugeffluxtransporteracrbofescherichiacoli
AT vargiuattiliovittorio molecularinteractionsofcarbapenemantibioticswiththemultidrugeffluxtransporteracrbofescherichiacoli
AT ruggeronepaolo molecularinteractionsofcarbapenemantibioticswiththemultidrugeffluxtransporteracrbofescherichiacoli