2. Academic Validation
  3. Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

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

  • Nat Commun. 2022 Jan 10;13(1):115. doi: 10.1038/s41467-021-27726-2.
Coline Plé # 1,  Heng-Keat Tam # 2 3,  Anais Vieira Da Cruz 4,  Nina Compagne 4,  Juan-Carlos Jiménez-Castellanos 1,  Reinke T Müller 2,  Elizabeth Pradel 1,  Wuen Ee Foong 2,  Giuliano Malloci 5,  Alexia Ballée 4,  Moritz A Kirchner 2,  Parisa Moshfegh 4,  Adrien Herledan 4,  Andrea Herrmann 2,  Benoit Deprez 4,  Nicolas Willand 4,  Attilio Vittorio Vargiu 5,  Klaas M Pos 6,  Marion Flipo 7,  Ruben C Hartkoorn 8
Affiliations

Affiliations

  • 1 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000, Lille, France.
  • 2 Institute of Biochemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438, Frankfurt am Main, Germany.
  • 3 Hengyang Medical School, University of South China, 421002, Hengyang, Hunan Province, China.
  • 4 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, F-59000, Lille, France.
  • 5 Department of Physics, University of Cagliari, 09042, Monserrato (Cagliari), Italy.
  • 6 Institute of Biochemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438, Frankfurt am Main, Germany. pos@em.uni-frankfurt.de.
  • 7 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177-Drugs and Molecules for Living Systems, F-59000, Lille, France. marion.flipo@univ-lille.fr.
  • 8 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000, Lille, France. ruben.hartkoorn@inserm.fr.
  • # Contributed equally.
PMID: 35013254 DOI: 10.1038/s41467-021-27726-2
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.

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