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.

中文翻译：

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环硼酸盐作为 KPC-2 β-内酰胺酶抑制的多功能支架

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 (SBL)，能够水解几乎所有 β-内酰胺类抗生素。我们比较了 vaborbactam（一种临床批准的单环硼酸盐）和 VNRX-5133（taniborbactam）（一种处于后期临床开发阶段的双环硼酸盐）对 KPC-2 的抑制作用。Vaborbactam 抑制作用是缓慢可逆的，而 taniborbactam 的解离速率表明复合物形成基本上不可逆，并且解离速率高 15 倍，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. 高分辨率 X 射线晶体结构揭示了这两种抑制剂与 KPC-2 密切相关的结合模式，差异仅在环内硼酸酯氧的定位上明显。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，并抢先阻止抑制剂抗性 KPC-2 变体的出现。