ArticleAntimicrobial agents and chemotherapy2014
Random mutagenesis of the multidrug transporter AcrB from Escherichia coli for identification of putative target residues of efflux pump inhibitors.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 39 citations in OpenAlex.
- Structural and functional diversity of Resistance-Nodulation-Division (RND) efflux pump transporters with implications for antimicrobial resistance.Microbiology and molecular biology reviews : MMBR · 2024Review
- Comparative reassessment of AcrB efflux inhibitors reveals differential impact of specific pump mutations on the activity of potent compounds.Microbiology spectrum · 2024Article
- AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism.BMB reports · 2023Review
- Deep dive into a drug pump.Nature chemical biology · 2023Article
- Deep mutational scan of a drug efflux pump reveals its structure-function landscape.Nature chemical biology · 2023Article
- Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria.Antibiotics (Basel, Switzerland) · 2023Review
- Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps.Nature communications · 2022Article
- β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward.Frontiers in microbiology · 2022Review
- An outbreak of extensively drug-resistant and hypervirulentFrontiers in cellular and infection microbiology · 2022Article
- Structure and function relationship of OqxB efflux pump from Klebsiella pneumoniae.Nature communications · 2021Article
- Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time.Antibiotics (Basel, Switzerland) · 2021Review
- Exploring the Contribution of the AcrB Homolog MdtF to Drug Resistance and Dye Efflux in a Multidrug ResistantAntibiotics (Basel, Switzerland) · 2021Article
- Limited Multidrug Resistance Efflux Pump Overexpression among Multidrug-Resistant Escherichia coli Strains of ST131.Antimicrobial agents and chemotherapy · 2021Article
- New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli uponAntimicrobial agents and chemotherapy · 2021Article
- Cryo-EM Structure and Molecular Dynamics Analysis of the Fluoroquinolone Resistant Mutant of the AcrB Transporter fromMicroorganisms · 2020Article
- Proof of an Outer Membrane Target of the Efflux Inhibitor Phe-Arg-β-Naphthylamide from Random Mutagenesis.Molecules (Basel, Switzerland) · 2019Article
- Exposure to Sub-inhibitory Concentrations of the Chemosensitizer 1-(1-Naphthylmethyl)-Piperazine Creates Membrane Destabilization in Multi-Drug ResistantFrontiers in microbiology · 2019Article
- Evidence of a Substrate-Discriminating Entrance Channel in the Lower Porter Domain of the Multidrug Resistance Efflux Pump AcrB.Antimicrobial agents and chemotherapy · 2016Article
- Novel Piperazine Arylideneimidazolones Inhibit the AcrAB-TolC Pump in Escherichia coli and Simultaneously Act as Fluorescent Membrane Probes in a Combined Real-Time Influx and Efflux Assay.Antimicrobial agents and chemotherapy · 2016Article
- Reversal of the Drug Binding Pocket Defects of the AcrB Multidrug Efflux Pump Protein of Escherichia coli.Journal of bacteriology · 2015Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Efflux is an important mechanism of bacterial multidrug resistance (MDR), and the inhibition of MDR pumps by efflux pump inhibitors (EPIs) could be a promising strategy to overcome MDR. 1-(1-Naphthylmethyl)-piperazine (NMP) and phenylalanine-arginine-β-naphthylamide (PAβN) are model EPIs with activity in various Gram-negative bacteria expressing AcrB, the major efflux pump of Escherichia coli, or similar homologous pumps of the resistance-nodulation-cell division class. The aim of the present study was to generate E. coli AcrB mutants resistant to the inhibitory action of the two model EPIs and to identify putative EPI target residues in order to better understand mechanisms of pump inhibition. Using an in vitro random mutagenesis approach focusing on the periplasmic domain of AcrB, we identified the double mutation G141D N282Y, which substantially compromised the synergistic activity of NMP with linezolid, was associated with similar intracellular linezolid concentrations in the presence and absence of NMP, and did not impair the intrinsic MICs of various pump substrates and dye accumulation. We propose that these mutations near the outer face of the distal substrate binding pocket reduce NMP trapping. Other residues found to be relevant for efflux inhibition by NMP were G288 and A279, but mutations at these sites also changed the susceptibility to several pump substrates. Unlike with NMP, we were unable to generate AcrB periplasmic domain mutants with resistance or partial resistance to the EPI activity of PAβN, which is consistent with the modes of action of PAβN differing from those of NMP.
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