文章基本信息

标题：Crystal structure of AmpC BER and molecular docking lead to the discovery of broad inhibition activities of halisulfates against β-lactamases
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作者：Bo-Gyeong Jeong ; Jung-Hyun Na ; Da-Woon Bae 等
期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2021
卷号：19
页码：145-152
DOI：10.1016/j.csbj.2020.12.015
出版社：Computational and Structural Biotechnology Journal
摘要：AmpC BER is an extended-spectrum (ES) class C β-lactamase with a two-amino-acid insertion in the H 10 helix region located at the boundary of the active site compared with its narrow spectrum progenitor. The crystal structure of the wild-type AmpC BER revealed that the insertion widens the active site by restructuring the flexible H 10 helix region, which is the structural basis for its ES activity. Besides, two sulfates originated from the crystallization solution were observed in the active site. The presence of sulfate-binding subsites, together with the recognition of ring-structured chemical scaffolds by AmpC BER, led us to perform in silico molecular docking experiments with halisulfates, natural products isolated from marine sponge. Inspired by the snug fit of halisulfates within the active site, we demonstrated that halisulfate 3 and 5 significantly inhibit ES class C β-lactamases. Especially, halisulfate 5 is comparable to avibactam in terms of inhibition efficiency; it inhibits the nitrocefin-hydrolyzing activity of AmpC BER with a K i value of 5.87 μM in a competitive manner. Furthermore, halisulfate 5 displayed moderate and weak inhibition activities against class A and class B/D enzymes, respectively. The treatment of β-lactamase inhibitors (BLIs) in combination with β-lactam antibiotics is a working strategy to cope with infections by pathogens producing ES β-lactamases. Considering the emergence and dissemination of enzymes insensitive to clinically-used BLIs, the broad inhibition spectrum and structural difference of halisulfates would be used to develop novel BLIs that can escape the bacterial resistance mechanism mediated by β-lactamases.
关键词：Crystal structure ; AmpC BER ; R2 loop ; Marine natural products ; Halisulfates ; Broad-spectrum competitive inhibitors