Journal Article

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

Tam, Heng-Keat, Hartkoorn, Ruben C., Pradel, Elizabeth, Herrmann, Andrea, Deprez, Benoit, Ballée, Alexia, Moshfegh, Parisa, Müller, Reinke T., Vieira Da Cruz, Anais, Flipo, Marion, Willand, Nicolas, Malloci, Giuliano, Compagne, Nina, Jiménez-Castellanos, Juan-Carlos, Kirchner, Moritz A., Vargiu, Attilio Vittorio, Plé, Coline, Foong, Wuen Ee, Pos, Klaas M., Herledan, Adrien

2022

Overview

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. Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, the authors identify pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through allosteric inhibition of its primary RND transporter.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/22 / 45/47 / 49/98 / 631/154/309/2144 / 631/154/556 / 631/326/22/1434 / 631/326/41/2536 / Allosteric properties / Allosteric Regulation - drug effects / Allosteric Site / Anti-Bacterial Agents - chemistry / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacteria / Bacterial Outer Membrane Proteins - antagonists & inhibitors / Bacterial Outer Membrane Proteins - chemistry / Bacterial Outer Membrane Proteins - genetics / Bacterial Outer Membrane Proteins - metabolism / Bacteriology / Biochemistry, Molecular Biology / Biological Transport - drug effects / Chemical Sciences / Crystallography, X-Ray / Cytoplasm / Drug Resistance, Multiple, Bacterial / E coli / Efflux / Escherichia coli - drug effects / Escherichia coli - genetics / Escherichia coli - metabolism / Escherichia coli Proteins - antagonists & inhibitors / Escherichia coli Proteins - chemistry / Escherichia coli Proteins - genetics / Escherichia coli Proteins - metabolism / Gene Expression / Gram-negative bacteria / Humanities and Social Sciences / Inhibitors / Kinases / Life Sciences / Lipoproteins - antagonists & inhibitors / Lipoproteins - chemistry / Lipoproteins - genetics / Lipoproteins - metabolism / Membrane Transport Proteins - chemistry / Membrane Transport Proteins - genetics / Membrane Transport Proteins - metabolism / Microbiology and Parasitology / Molecular dynamics / Molecular Dynamics Simulation / multidisciplinary / Multidrug Resistance-Associated Proteins - antagonists & inhibitors / Multidrug Resistance-Associated Proteins - chemistry / Multidrug Resistance-Associated Proteins - genetics / Multidrug Resistance-Associated Proteins - metabolism / Mutation / Oligopeptides - chemistry / Oligopeptides - pharmacology / Organic chemistry / Oxacillin - chemistry / Oxacillin - pharmacology / Piperazines - chemical synthesis / Piperazines - pharmacology / Promoter Regions, Genetic / Protein Binding / Protein Conformation, alpha-Helical / Protein Conformation, beta-Strand / Protein Interaction Domains and Motifs / Pyridines - chemical synthesis / Pyridines - pharmacology / Science / Science (multidisciplinary) / Structure-Activity Relationship