Novel non-β-lactam inhibitor of β-lactamase TEM-171 based on acylated phenoxyaniline

The microbial resistance to antibiotics is a genuine global threat. Consequently, a search of new inhibitors remains of acute importance due to the increasing spread of multidrug resistance. Here we present a new type of non-β-lactam β-lactamase inhibitor PA-34 based on natural phenoxyaniline, ident...

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Bibliographic Details
Published in:Biochimie 2017-01, Vol.132, p.45-53
Main Authors: Grigorenko, V.G., Andreeva, I.P., Rubtsova, M.Yu, Deygen, I.M., Antipin, R.L., Majouga, A.G., Egorov, A.M., Beshnova, D.A., Kallio, J., Hackenberg, C., Lamzin, V.S.
Format: Article
Language:English
Subjects:
Acylation
Aniline Compounds - chemistry
Aniline Compounds - pharmacology
Antibiotic resistance
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
beta-Lactamase Inhibitors - chemistry
beta-Lactamase Inhibitors - pharmacology
beta-Lactamases - chemistry
beta-Lactamases - metabolism
Binding Sites
Catalytic Domain
Computer Simulation
Drug Discovery - methods
Electrophoresis, Polyacrylamide Gel
Fluorescence
Kinetics
Lead discovery
Molecular Docking Simulation
Molecular Structure
Non-β-lactam inhibitor
Recombinant β-lactamase TEM
Spectroscopy, Fourier Transform Infrared - methods
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Summary:The microbial resistance to antibiotics is a genuine global threat. Consequently, a search of new inhibitors remains of acute importance due to the increasing spread of multidrug resistance. Here we present a new type of non-β-lactam β-lactamase inhibitor PA-34 based on natural phenoxyaniline, identified using computer-assisted screening of scaffolds related to those of known low-affinity inhibitors. The compound displays reversible competitive inhibition of bacterial β-lactamase TEM-171, with a Ki of 88 μM. Using enzyme kinetics, infra-red spectroscopy, fluorescence quenching and computer docking, we propose that the inhibitor binds at the entrance to the enzyme active site. This is a novel inhibition mechanism compared to binding covalently to the catalytic serine in the active site or non-covalently to the allosteric site. The residues involved in binding the inhibitor are conserved among molecular class A β-lactamases. The identified compound and its proposed binding mode may have a potential for a regulation of the catalytic activity of a wide range of class A β-lactamases. We also hypothesise that the presented route for finding non-β-lactam compounds may be an effective and durable approach for combating bacterial antibiotic resistance. •New type of non-β-lactam β-lactamase inhibitor based on phenoxyaniline is described.•A new binding mode – blocking access to the active site is proposed.•Binding of PA-34 inhibitor is assisted by at least two highly conserved residues.•These residues (G242 and Y105) are conserved among molecular class A β-lactamases.
ISSN:0300-9084
1638-6183
DOI:10.1016/j.biochi.2016.10.011