Cyclic boronates as versatile scaffolds for KPC-2 ß-lactamase inhibition.
Cyclic boronates as versatile scaffolds for KPC-2 ß-lactamase inhibition.
复制标题
环状硼酸盐作为 KPC-2 α-内酰胺酶抑制的多功能支架。
DOI：
10.1039/c9md00557a
复制
发表时间：
2020
影响因子：
4.1
通讯作者：
Tooke CL
中科院分区：
文献类型：
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作者：
Tooke CL
肺炎克雷伯菌碳青霉烯酶-2(Kpc-2)是一种丝氨酸-β-内酰胺酶，能降解几乎所有的β-内酰胺类抗生素。我们比较了临床批准的单环硼酸盐vborbactam和双环硼酸盐VNRX-5133(Taniborbactam)在临床开发后期对KPC-2的抑制作用。瓦博巴坦的抑制是缓慢可逆的，而塔尼博巴坦的OFF率表明基本上不可逆的复合体形成和15倍以上的On率，尽管两者都增强了β-内酰胺对表达kpc-2的肺炎克雷伯菌的活性。高分辨X射线晶体结构显示，这两种抑制剂与KPC-2的结合模式密切相关，只有内环硼酸酯氧的位置存在明显差异。结果表明，双环硼酸盐支架既是一种高效、持久的KPC-2抑制剂，又能够支持进一步的迭代，从而提高针对特定酶靶标的效力，并先发制人地出现具有抑制剂抗性的KPC-2变体。
Klebsiella pneumoniae carbapenemase-2 (KPC-2) is a serine-β-lactamase (SBL) capable of hydrolysing almost all β-lactam antibiotics. We compare KPC-2 inhibition by vaborbactam, a clinically-approved monocyclic boronate, and VNRX-5133 (taniborbactam), a bicyclic boronate in late-stage clinical development. Vaborbactam inhibition is slowly reversible, whereas taniborbactam has an off-rate indicating essentially irreversible complex formation and a 15-fold higher on-rate, although both potentiate β-lactam activity against KPC-2-expressing K. pneumoniae. High resolution X-ray crystal structures reveal closely related binding modes for both inhibitors to KPC-2, with differences apparent only in positioning of the endocyclic boronate ester oxygen. The results indicate the bicyclic boronate scaffold as both an efficient, long-lasting, KPC-2 inhibitor and capable of supporting further iterations that may improve potency against specific enzyme targets and pre-empt the emergence of inhibitor resistant KPC-2 variants.