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Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms
Upon antibiotic stress Gram-negative pathogens deploy resistance-nodulation-cell division-type tripartite efflux pumps. These include a H(+)/drug antiporter module that recognizes structurally diverse substances, including antibiotics. Here, we show the 3.5 Å structure of subunit AdeB from the Acine...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617272/ https://www.ncbi.nlm.nih.gov/pubmed/34824229 http://dx.doi.org/10.1038/s41467-021-27146-2 |
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author | Ornik-Cha, Alina Wilhelm, Julia Kobylka, Jessica Sjuts, Hanno Vargiu, Attilio V. Malloci, Giuliano Reitz, Julian Seybert, Anja Frangakis, Achilleas S. Pos, Klaas M. |
author_facet | Ornik-Cha, Alina Wilhelm, Julia Kobylka, Jessica Sjuts, Hanno Vargiu, Attilio V. Malloci, Giuliano Reitz, Julian Seybert, Anja Frangakis, Achilleas S. Pos, Klaas M. |
author_sort | Ornik-Cha, Alina |
collection | PubMed |
description | Upon antibiotic stress Gram-negative pathogens deploy resistance-nodulation-cell division-type tripartite efflux pumps. These include a H(+)/drug antiporter module that recognizes structurally diverse substances, including antibiotics. Here, we show the 3.5 Å structure of subunit AdeB from the Acinetobacter baumannii AdeABC efflux pump solved by single-particle cryo-electron microscopy. The AdeB trimer adopts mainly a resting state with all protomers in a conformation devoid of transport channels or antibiotic binding sites. However, 10% of the protomers adopt a state where three transport channels lead to the closed substrate (deep) binding pocket. A comparison between drug binding of AdeB and Escherichia coli AcrB is made via activity analysis of 20 AdeB variants, selected on basis of side chain interactions with antibiotics observed in the AcrB periplasmic domain X-ray co-structures with fusidic acid (2.3 Å), doxycycline (2.1 Å) and levofloxacin (2.7 Å). AdeABC, compared to AcrAB-TolC, confers higher resistance to E. coli towards polyaromatic compounds and lower resistance towards antibiotic compounds. |
format | Online Article Text |
id | pubmed-8617272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86172722021-12-10 Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms Ornik-Cha, Alina Wilhelm, Julia Kobylka, Jessica Sjuts, Hanno Vargiu, Attilio V. Malloci, Giuliano Reitz, Julian Seybert, Anja Frangakis, Achilleas S. Pos, Klaas M. Nat Commun Article Upon antibiotic stress Gram-negative pathogens deploy resistance-nodulation-cell division-type tripartite efflux pumps. These include a H(+)/drug antiporter module that recognizes structurally diverse substances, including antibiotics. Here, we show the 3.5 Å structure of subunit AdeB from the Acinetobacter baumannii AdeABC efflux pump solved by single-particle cryo-electron microscopy. The AdeB trimer adopts mainly a resting state with all protomers in a conformation devoid of transport channels or antibiotic binding sites. However, 10% of the protomers adopt a state where three transport channels lead to the closed substrate (deep) binding pocket. A comparison between drug binding of AdeB and Escherichia coli AcrB is made via activity analysis of 20 AdeB variants, selected on basis of side chain interactions with antibiotics observed in the AcrB periplasmic domain X-ray co-structures with fusidic acid (2.3 Å), doxycycline (2.1 Å) and levofloxacin (2.7 Å). AdeABC, compared to AcrAB-TolC, confers higher resistance to E. coli towards polyaromatic compounds and lower resistance towards antibiotic compounds. Nature Publishing Group UK 2021-11-25 /pmc/articles/PMC8617272/ /pubmed/34824229 http://dx.doi.org/10.1038/s41467-021-27146-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ornik-Cha, Alina Wilhelm, Julia Kobylka, Jessica Sjuts, Hanno Vargiu, Attilio V. Malloci, Giuliano Reitz, Julian Seybert, Anja Frangakis, Achilleas S. Pos, Klaas M. Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms |
title | Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms |
title_full | Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms |
title_fullStr | Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms |
title_full_unstemmed | Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms |
title_short | Structural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms |
title_sort | structural and functional analysis of the promiscuous acrb and adeb efflux pumps suggests different drug binding mechanisms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617272/ https://www.ncbi.nlm.nih.gov/pubmed/34824229 http://dx.doi.org/10.1038/s41467-021-27146-2 |
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