NDM-1 can hydrolyze nearly all available β-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of ¹⁵N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.

NDM-1可以水解几乎所有可用的β-内酰胺抗生素，包括碳青霉烯。产生NDM-1的细菌菌株是全世界的威胁。寻找一种有效的NDM-1抑制剂用于临床仍是非常具有挑战性的。在我们的研究中，我们使用了富含金属结合药效团（MBP）的虚拟片段库来筛选NDM-1命中。SPR筛选有助于验证MBP虚拟命中，并鉴定了新的NDM-1结合剂和弱抑制剂A1。一项对^15个N标记的NDM-1的溶液NMR研究表明，A1干扰了NDM-1活性口袋中与第二个锌离子（Zn2）配位的所有三个残基。摄动仅在锌离子存在下发生，表明A1绑定到Zn2。基于A1的支架，我们设计并合成了一系列NDM-1抑制剂。几种化合物与美罗培南对产生NDM-1的肺炎克雷伯菌显示协同抗菌活性。