کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5509148 1538400 2017 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Novel non-β-lactam inhibitor of β-lactamase TEM-171 based on acylated phenoxyaniline
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Novel non-β-lactam inhibitor of β-lactamase TEM-171 based on acylated phenoxyaniline
چکیده انگلیسی


- 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.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimie - Volume 132, January 2017, Pages 45-53
نویسندگان
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