Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2022

Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

Abstract

Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.
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Origin : Publication funded by an institution

Dates and versions

hal-03521512 , version 1 (19-02-2024)

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Coline Plé, Heng-Keat Tam, Anais Vieira da Cruz, Nina Compagne, Juan-Carlos Jiménez-Castellanos, et al.. Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps. Nature Communications, 2022, 13 (1), pp.115. ⟨10.1038/s41467-021-27726-2⟩. ⟨hal-03521512⟩
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