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. Epub 2023 Dec 20.


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.

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / pharmacology
  • Anti-Bacterial Agents* / therapeutic use
  • Escherichia coli
  • Escherichia coli Proteins* / metabolism
  • Escherichia coli Proteins* / pharmacology
  • Klebsiella pneumoniae / metabolism
  • Mice
  • Multidrug Resistance-Associated Proteins / metabolism
  • Multidrug Resistance-Associated Proteins / pharmacology


  • Anti-Bacterial Agents
  • Escherichia coli Proteins
  • AcrB protein, E coli
  • Multidrug Resistance-Associated Proteins