Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps
Malloci G.;Vargiu A. V.;
2022-01-01
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.File | Size | Format | |
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2022-AcrB-pyridilpiperazine-based_allosteric_inhibitors_NatCommun_13.115.pdf open access
Type: versione editoriale
Size 1.68 MB
Format Adobe PDF
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1.68 MB | Adobe PDF | View/Open |
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