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Details

Autor(en) / Beteiligte
Titel
Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps
Ist Teil von
  • Nature communications, 2022-01, Vol.13 (1), p.115-115, Article 115
Ort / Verlag
London: Nature Publishing Group UK
Erscheinungsjahr
2022
Quelle
MEDLINE
Beschreibungen/Notizen
  • 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.
Sprache
Englisch
Identifikatoren
ISSN: 2041-1723
eISSN: 2041-1723
DOI: 10.1038/s41467-021-27726-2
Titel-ID: cdi_doaj_primary_oai_doaj_org_article_2d5e83c99b5c4265bf969d47fed84ba5
Format
Schlagworte
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

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