Optimization of pyridylpiperazine-based inhibitors of the Escherichia coli AcrAB-TolC efflux pump.

Multidrug-resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a critical driver. We have previously described pyridylpiperazines as a novel class of allosteric inhibitors of E. coli AcrB which bind to a unique site in the protein transmembrane domain, allowing for the potentiation of antibiotic activity. Here, we show a rational optimization of pyridylpiperazines by modifying three specific derivatization points of the pyridine core to improve the potency and the pharmacokinetic properties of this chemical series. In particular, this work found that the introduction of a primary amine to the pyridine through ester (29, BDM91270) or oxadiazole (44, BDM91514) based linkers allowed for analogues with improved antibiotic boosting potency through AcrB inhibition. In vitro studies, using genetically engineered mutants, showed that this improvement in potency is mediated through novel interactions with distal acidic residues of the AcrB binding pocket. Of the two leads, compound 44 was found to have favorable physico-chemical properties and suitable plasma and microsomal stability. Together, this work expands the current structure-activity relationship data on pyridylpiperazine efflux pump inhibitors, and provides a promising step towards future in vivo proof of concept of pyridylpiperazines as antibiotic potentiators.

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Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marion Flipo has patent Gram-negative bacteria efflux pump inhibitors pending to Inserm transfert. Ruben Hartkoorn has patent Gram-negative bacteria efflux pump inhibitors pending to Inserm transfert. Nina Compagne has patent Gram-negative bacteria efflux pump inhibitors pending to Inserm transfert. Nicolas Willand has patent Gram-negative bacteria efflux pump inhibitors pending to Inserm transfert. Anais Vieira Da Cruz has patent Gram-negative bacteria efflux pump inhibitors pending to Inserm transfert. Juan-Carlos Jimenez-Castellanos has patent Gram-negative bacteria efflux pump inhibitors pending to Inserm transfert.