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

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. Kirchner, Parisa Moshfegh, Adrien Herledan, Andrea Herrmann, Benoit Deprez, Nicolas Willand, Attilio Vittorio Vargiu, Klaas M. Pos (), Marion Flipo () and Ruben C. Hartkoorn ()
Additional contact information
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27726-2

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DOI: 10.1038/s41467-021-27726-2

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