2. Academic Validation
  3. Pyridylpiperazine efflux pump inhibitor boosts in vivo antibiotic efficacy against K. pneumoniae

Pyridylpiperazine efflux pump inhibitor boosts in vivo antibiotic efficacy against K. pneumoniae

  • EMBO Mol Med. 2024 Jan;16(1):93-111. doi: 10.1038/s44321-023-00007-9.
Anais Vieira Da Cruz # 1,  Juan-Carlos Jiménez-Castellanos # 2,  Clara Börnsen # 3,  Laurye Van Maele # 2,  Nina Compagne 1,  Elizabeth Pradel 2,  Reinke T Müller 4,  Virginie Meurillon 1,  Daphnée Soulard 2,  Catherine Piveteau 1,  Alexandre Biela 1,  Julie Dumont 1,  Florence Leroux 1 5,  Benoit Deprez 1,  Nicolas Willand 1,  Klaas M Pos # 6,  Achilleas S Frangakis # 7,  Ruben C Hartkoorn # 8,  Marion Flipo # 9
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France.
  • 2 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000, Lille, France.
  • 3 Buchmann Institute for Molecular Life Sciences and Institute for Biophysics, Goethe University Frankfurt, Max-von-Laue-Str. 15, D-60438, Frankfurt am Main, Germany.
  • 4 Institute of Biochemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438, Frankfurt am Main, Germany.
  • 5 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur Lille, US 41-UAR 2014-PLBS, F-59000, Lille, France.
  • 6 Institute of Biochemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438, Frankfurt am Main, Germany. pos@em.uni-frankfurt.de.
  • 7 Buchmann Institute for Molecular Life Sciences and Institute for Biophysics, Goethe University Frankfurt, Max-von-Laue-Str. 15, D-60438, Frankfurt am Main, Germany. achilleas.frangakis@biophysik.org.
  • 8 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000, Lille, France. ruben.hartkoorn@inserm.fr.
  • 9 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France. marion.flipo@univ-lille.fr.
  • # Contributed equally.
PMID: 38177534 DOI: 10.1038/s44321-023-00007-9
Abstract

Antimicrobial resistance is a global problem, rendering conventional treatments less effective and requiring innovative strategies to combat this growing threat. The tripartite AcrAB-TolC efflux pump is the dominant constitutive system by which Enterobacterales like Escherichia coli and Klebsiella pneumoniae extrude Antibiotics. Here, we describe the medicinal chemistry development and drug-like properties of BDM91288, a pyridylpiperazine-based AcrB efflux pump inhibitor. In vitro evaluation of BDM91288 confirmed it to potentiate the activity of a panel of Antibiotics against K. pneumoniae as well as revert clinically relevant Antibiotic resistance mediated by acrAB-tolC overexpression. Using cryo-EM, BDM91288 binding to the transmembrane region of K. pneumoniae AcrB was confirmed, further validating the mechanism of action of this inhibitor. Finally, proof of concept studies demonstrated that oral administration of BDM91288 significantly potentiated the in vivo efficacy of levofloxacin treatment in a murine model of K. pneumoniae lung Infection.

Keywords

AcrAB-TolC; Antibiotic Efflux Pump; Antimicrobial Resistance; Cryo-EM; Efflux Pump Inhibitor.

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