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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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.
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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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