Enhancing antibiotic activity against Escherichia coli and Klebsiella pneumoniae with optimised pyridylpiperazine AcrAB-TolC efflux pump inhibitors
Abstract
Multidrug-resistant Enterobacterales, including Escherichia coli and Klebsiella pneumoniae, are classified as critical priority pathogens by the World Health Organization. A major contributor to resistance in these Gram-negative bacteria is the overexpression of the broad-spectrum RND-efflux pump AcrAB-TolC. To counteract efflux-mediated resistance, a series of pyridylpiperazine inhibitors was previously reported and we demonstrated that these compounds bind to a novel allosteric pocket within the transmembrane domain of AcrB in both E. coli and K. pneumoniae. Here, we synthesised 28 new analogues to explore structure-activity relationships around the benzylamine moiety, with the aim of improving the drug-like properties of the starting compound 4 (BDM91531). Replacement of the benzylamine group at position 6 of the quinoline scaffold resulted in compounds with slightly lower potency, but with the beneficial absence of intrinsic antibacterial activity and reduced cytotoxicity. Studies using E. coli AcrB mutants confirmed the previously proposed binding mode of this chemical series. Evaluation of physico-chemical properties and microsomal stability enabled the identification of compound 35 (BDM92641), bearing a thiazole ring, which displayed favourable physico-chemical and in vitro pharmacokinetic properties. Notably, this compound potentiates the activity of several antibiotic classes against E. coli and K. pneumoniae. Overall, this work provides deeper insight into the structure-activity relationships of pyridylpiperazine-based efflux pump inhibitors and represents a significant step toward their future in vivo validation as antibiotic adjuvants.
Related
- Optimized alkyne-modified pyridylpiperazine efflux pump inhibitors overcome intrinsic macrolide resistance in multidrug-resistant Klebsiella pneumoniae isolates
- Experimental and Monte Carlo Insights into the Biofilm Control of Klebsiella pneumoniae Using Green-Synthesized Ag/Ni(OH)2/Clove Nanocomposites
- The Effect of a Fullerene Water Suspension on the Growth, Cell Viability, and Membrane Integrity of Escherichia coli B23
- Quaternary structures of Streptococcus pneumoniae nucleoside diphosphate kinase: From hexamers to supramolecular assemblies
- Development and Optimization of a Molecularly Imprinted Polymer for Electrochemical Detection of Escherichia coli
BibTeX
@article{meurillon2026enhancing,
title = {{Enhancing antibiotic activity against Escherichia coli and Klebsiella pneumoniae with optimised pyridylpiperazine AcrAB-TolC efflux pump inhibitors}},
author = {Virginie Meurillon and Juan-Carlos Jiménez-Castellanos and Anais Vieira da Cruz and Cécilia Sobieski and Léa Lèbre and Catherine Piveteau and Valérie Landry and Florence Leroux and Benoit Deprez and Nicolas Willand and Ruben C. Hartkoorn and Marion Flipo},
journal = {European Journal of Medicinal Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.ejmech.2026.119200},
url = {https://hal.science/hal-05767646v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Enhancing antibiotic activity against Escherichia coli and Klebsiella pneumoniae with optimised pyridylpiperazine AcrAB-TolC efflux pump inhibitors
AU - Virginie Meurillon
AU - Juan-Carlos Jiménez-Castellanos
AU - Anais Vieira da Cruz
AU - Cécilia Sobieski
AU - Léa Lèbre
AU - Catherine Piveteau
AU - Valérie Landry
AU - Florence Leroux
AU - Benoit Deprez
AU - Nicolas Willand
AU - Ruben C. Hartkoorn
AU - Marion Flipo
PY - 2026
DA - 2026/09/28
JO - European Journal of Medicinal Chemistry
DO - 10.1016/j.ejmech.2026.119200
UR - https://hal.science/hal-05767646v1
AB - Multidrug-resistant Enterobacterales, including Escherichia coli and Klebsiella pneumoniae, are classified as critical priority pathogens by the World Health Organization. A major contributor to resistance in these Gram-negative bacteria is the overexpression of the broad-spectrum RND-efflux pump AcrAB-TolC. To counteract efflux-mediated resistance, a series of pyridylpiperazine inhibitors was previously reported and we demonstrated that these compounds bind to a novel allosteric pocket within the transmembrane domain of AcrB in both E. coli and K. pneumoniae. Here, we synthesised 28 new analogues to explore structure-activity relationships around the benzylamine moiety, with the aim of improving the drug-like properties of the starting compound 4 (BDM91531). Replacement of the benzylamine group at position 6 of the quinoline scaffold resulted in compounds with slightly lower potency, but with the beneficial absence of intrinsic antibacterial activity and reduced cytotoxicity. Studies using E. coli AcrB mutants confirmed the previously proposed binding mode of this chemical series. Evaluation of physico-chemical properties and microsomal stability enabled the identification of compound 35 (BDM92641), bearing a thiazole ring, which displayed favourable physico-chemical and in vitro pharmacokinetic properties. Notably, this compound potentiates the activity of several antibiotic classes against E. coli and K. pneumoniae. Overall, this work provides deeper insight into the structure-activity relationships of pyridylpiperazine-based efflux pump inhibitors and represents a significant step toward their future in vivo validation as antibiotic adjuvants.
SN - 0223-5234
SN - 1768-3254
ER -