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Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps
Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Charact...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749003/ https://www.ncbi.nlm.nih.gov/pubmed/35013254 http://dx.doi.org/10.1038/s41467-021-27726-2 |
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author | Plé, Coline Tam, Heng-Keat Vieira Da Cruz, Anais Compagne, Nina Jiménez-Castellanos, Juan-Carlos Müller, Reinke T. Pradel, Elizabeth Foong, Wuen Ee Malloci, Giuliano Ballée, Alexia Kirchner, Moritz A. Moshfegh, Parisa Herledan, Adrien Herrmann, Andrea Deprez, Benoit Willand, Nicolas Vargiu, Attilio Vittorio Pos, Klaas M. Flipo, Marion Hartkoorn, Ruben C. |
author_facet | Plé, Coline Tam, Heng-Keat Vieira Da Cruz, Anais Compagne, Nina Jiménez-Castellanos, Juan-Carlos Müller, Reinke T. Pradel, Elizabeth Foong, Wuen Ee Malloci, Giuliano Ballée, Alexia Kirchner, Moritz A. Moshfegh, Parisa Herledan, Adrien Herrmann, Andrea Deprez, Benoit Willand, Nicolas Vargiu, Attilio Vittorio Pos, Klaas M. Flipo, Marion Hartkoorn, Ruben C. |
author_sort | Plé, Coline |
collection | PubMed |
description | Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump. |
format | Online Article Text |
id | pubmed-8749003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87490032022-01-20 Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps Plé, Coline Tam, Heng-Keat Vieira Da Cruz, Anais Compagne, Nina Jiménez-Castellanos, Juan-Carlos Müller, Reinke T. Pradel, Elizabeth Foong, Wuen Ee Malloci, Giuliano Ballée, Alexia Kirchner, Moritz A. Moshfegh, Parisa Herledan, Adrien Herrmann, Andrea Deprez, Benoit Willand, Nicolas Vargiu, Attilio Vittorio Pos, Klaas M. Flipo, Marion Hartkoorn, Ruben C. Nat Commun Article Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump. Nature Publishing Group UK 2022-01-10 /pmc/articles/PMC8749003/ /pubmed/35013254 http://dx.doi.org/10.1038/s41467-021-27726-2 Text en © The Author(s) 2022 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 Plé, Coline Tam, Heng-Keat Vieira Da Cruz, Anais Compagne, Nina Jiménez-Castellanos, Juan-Carlos Müller, Reinke T. Pradel, Elizabeth Foong, Wuen Ee Malloci, Giuliano Ballée, Alexia Kirchner, Moritz A. Moshfegh, Parisa Herledan, Adrien Herrmann, Andrea Deprez, Benoit Willand, Nicolas Vargiu, Attilio Vittorio Pos, Klaas M. Flipo, Marion Hartkoorn, Ruben C. Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps |
title | Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps |
title_full | Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps |
title_fullStr | Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps |
title_full_unstemmed | Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps |
title_short | Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps |
title_sort | pyridylpiperazine-based allosteric inhibitors of rnd-type multidrug efflux pumps |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749003/ https://www.ncbi.nlm.nih.gov/pubmed/35013254 http://dx.doi.org/10.1038/s41467-021-27726-2 |
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