Abstract：
: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.
journal_name
Biochimiejournal_title
Biochimieauthors
Grigorenko VG,Andreeva IP,Rubtsova MY,Deygen IM,Antipin RL,Majouga AG,Egorov AM,Beshnova DA,Kallio J,Hackenberg C,Lamzin VSdoi
10.1016/j.biochi.2016.10.011subject
Has Abstractpub_date
2017-01-01 00:00:00pages
45-53eissn
0300-9084issn
1638-6183pii
S0300-9084(16)30285-1journal_volume
132pub_type
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