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TitlePyridylpiperazine efflux pump inhibitor boosts in vivo antibiotic efficacy against K. pneumoniae.
Journal, issue, pagesEMBO Mol Med, Vol. 16, Issue 1, Page 93-9111, Year 2024
Publish dateDec 20, 2023
AuthorsAnais Vieira Da Cruz / Juan-Carlos Jiménez-Castellanos / Clara Börnsen / Laurye Van Maele / Nina Compagne / Elizabeth Pradel / Reinke T Müller / Virginie Meurillon / Daphnée Soulard / Catherine Piveteau / Alexandre Biela / Julie Dumont / Florence Leroux / Benoit Deprez / Nicolas Willand / Klaas M Pos / Achilleas S Frangakis / Ruben C Hartkoorn / Marion Flipo /
PubMed AbstractAntimicrobial 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 ...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.
External linksEMBO Mol Med / PubMed:38177534 / PubMed Central
MethodsEM (single particle)
Resolution2.97 Å
Structure data

17350

8p1i

EMDB-17350, PDB-8p1i:
Single particle cryo-EM co-structure of Klebsiella pneumoniae AcrB with the BDM91288 efflux pump inhibitor at 2.97 Angstrom resolution
Method: EM (single particle) / Resolution: 2.97 Å

Chemicals

ChemComp-WQW:
3-chloranyl-2,6-di(piperazin-4-ium-1-yl)quinoline

ChemComp-WR6:
[(2~{R})-1-[[(2~{R})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-3-undecanoyloxy-propan-2-yl] tricosanoate

ChemComp-PG8:
1,2-DIOCTANOYL-SN-GLYCERO-3-[PHOSPHO-RAC-(1-GLYCEROL)

Source
  • klebsiella pneumoniae subsp. pneumoniae dsm 30104 = jcm 1662 = nbrc 14940 (bacteria)
KeywordsTRANSPORT PROTEIN / Efflux Pump Inhibitor / Transmembrane Binding / Antibiotic Resistance

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