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Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

Author

Listed:
  • Coline Plé

    (Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille)

  • Heng-Keat Tam

    (Goethe-University Frankfurt
    University of South China)

  • Anais Vieira Da Cruz

    (Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems)

  • Nina Compagne

    (Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems)

  • Juan-Carlos Jiménez-Castellanos

    (Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille)

  • Reinke T. Müller

    (Goethe-University Frankfurt)

  • Elizabeth Pradel

    (Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille)

  • Wuen Ee Foong

    (Goethe-University Frankfurt)

  • Giuliano Malloci

    (University of Cagliari)

  • Alexia Ballée

    (Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems)

  • Moritz A. Kirchner

    (Goethe-University Frankfurt)

  • Parisa Moshfegh

    (Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems)

  • Adrien Herledan

    (Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems)

  • Andrea Herrmann

    (Goethe-University Frankfurt)

  • Benoit Deprez

    (Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems)

  • Nicolas Willand

    (Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems)

  • Attilio Vittorio Vargiu

    (University of Cagliari)

  • Klaas M. Pos

    (Goethe-University Frankfurt)

  • Marion Flipo

    (Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems)

  • Ruben C. Hartkoorn

    (Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019—UMR 9017—CIIL—Center for Infection and Immunity of Lille)

Abstract

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.

Suggested Citation

  • Coline Plé & Heng-Keat Tam & Anais Vieira Da Cruz & Nina Compagne & Juan-Carlos Jiménez-Castellanos & Reinke T. Müller & Elizabeth Pradel & Wuen Ee Foong & Giuliano Malloci & Alexia Ballée & Moritz A., 2022. "Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27726-2
    DOI: 10.1038/s41467-021-27726-2
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    References listed on IDEAS

    as
    1. Laetitia Daury & François Orange & Jean-Christophe Taveau & Alice Verchère & Laura Monlezun & Céline Gounou & Ravi K. R. Marreddy & Martin Picard & Isabelle Broutin & Klaas M. Pos & Olivier Lambert, 2016. "Tripartite assembly of RND multidrug efflux pumps," Nature Communications, Nature, vol. 7(1), pages 1-8, April.
    2. Marie Glavier & Dhenesh Puvanendran & Dimitri Salvador & Marion Decossas & Gilles Phan & Cyril Garnier & Elisa Frezza & Quentin Cece & Guy Schoehn & Martin Picard & Jean-Christophe Taveau & Laetitia D, 2020. "Antibiotic export by MexB multidrug efflux transporter is allosterically controlled by a MexA-OprM chaperone-like complex," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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