Novel non-β-lactam inhibitor of β-lactamase TEM-171 based on acylated phenoxyaniline
| Autor: | R. L. Antipin, Alexander G. Majouga, Johanna Kallio, I.M. Deygen, Daria A. Beshnova, I. P. Andreeva, Vitaly G. Grigorenko, M. Yu. Rubtsova, Claudia Hackenberg, Alexey M. Egorov, Victor S. Lamzin |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Non-β-lactam inhibitor Stereochemistry Antibiotic resistance Acylation Allosteric regulation Biochemistry Fluorescence beta-Lactamases Serine 03 medical and health sciences chemistry.chemical_compound Non-competitive inhibition Bacterial Proteins Catalytic Domain Drug Discovery Spectroscopy Fourier Transform Infrared Computer Simulation Enzyme kinetics Recombinant β-lactamase TEM Lead discovery Aniline Compounds Binding Sites 030102 biochemistry & molecular biology biology Molecular Structure Active site General Medicine Multiple drug resistance Molecular Docking Simulation Kinetics 030104 developmental biology chemistry Docking (molecular) biology.protein Lactam Electrophoresis Polyacrylamide Gel beta-Lactamase Inhibitors |
| Zdroj: | Biochimie. 132:45-53 |
| ISSN: | 0300-9084 |
| DOI: | 10.1016/j.biochi.2016.10.011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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