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Publication Abstract from PubMed

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.

Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps.,Ple C, Tam HK, Vieira Da Cruz A, Compagne N, Jimenez-Castellanos JC, Muller RT, Pradel E, Foong WE, Malloci G, Ballee A, Kirchner MA, Moshfegh P, Herledan A, Herrmann A, Deprez B, Willand N, Vargiu AV, Pos KM, Flipo M, Hartkoorn RC Nat Commun. 2022 Jan 10;13(1):115. doi: 10.1038/s41467-021-27726-2. PMID:35013254^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.