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比阿培南与VIM金属β-内酰胺酶和丝氨酸β-内酰胺酶KPC-2反应的研究

Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2.

作者信息

Lucic Anka, Malla Tika R, Calvopiña Karina, Tooke Catherine L, Brem Jürgen, McDonough Michael A, Spencer James, Schofield Christopher J

机构信息

Chemistry Research Laboratory, The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UK.

Biomedical Sciences Building, School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.

出版信息

Antibiotics (Basel). 2022 Mar 16;11(3):396. doi: 10.3390/antibiotics11030396.

Abstract

Carbapenems are important antibacterials and are both substrates and inhibitors of some β-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-β-lactamases VIM-1 and VIM-2 and the class A serine-β-lactamase KPC-2. X-ray diffraction studies with VIM-2 crystals treated with biapenem reveal the opening of the β-lactam ring to form a mixture of the (2)-imine and enamine complexed at the active site. NMR studies on the reactions of biapenem with VIM-1, VIM-2, and KPC-2 reveal the formation of hydrolysed enamine and (2)- and (2)-imine products. The combined results support the proposal that SBL/MBL-mediated carbapenem hydrolysis results in a mixture of tautomerizing enamine and (2)- and (2)-imine products, with the thermodynamically favoured (2)-imine being the major observed species over a relatively long-time scale. The results suggest that prolonging the lifetimes of β-lactamase carbapenem complexes by optimising tautomerisation of the nascently formed enamine to the (2)-imine and likely more stable (2)-imine tautomer is of interest in developing improved carbapenems.

摘要

碳青霉烯类是重要的抗菌药物,既是某些β-内酰胺酶的底物,也是其抑制剂。我们报告了关于不寻常的碳青霉烯类药物比阿培南与B1亚类金属β-内酰胺酶VIM-1和VIM-2以及A类丝氨酸β-内酰胺酶KPC-2反应的研究。对比阿培南处理过的VIM-2晶体进行的X射线衍射研究表明,β-内酰胺环打开,在活性位点形成(2)-亚胺和烯胺复合物的混合物。对比阿培南与VIM-1、VIM-2和KPC-2反应的核磁共振研究表明,形成了水解烯胺以及(2)-和(2)-亚胺产物。综合结果支持以下观点:SBL/MBL介导的碳青霉烯水解会产生互变异构的烯胺以及(2)-和(2)-亚胺产物的混合物,在相对较长的时间尺度上,热力学上更有利的(2)-亚胺是主要观察到的物种。结果表明,通过优化新生烯胺向(2)-亚胺以及可能更稳定的(2)-亚胺互变异构体的互变异构作用来延长β-内酰胺酶碳青霉烯复合物的寿命,对于开发改进的碳青霉烯类药物具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4806/8944426/e17c7143ea7c/antibiotics-11-00396-g001.jpg

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