Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, PR China.
Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 72101, Shaanxi Province, PR China.
Bioorg Med Chem. 2021 May 15;38:116128. doi: 10.1016/j.bmc.2021.116128. Epub 2021 Apr 8.
To combat the superbug infection caused by metallo-β-lactamases (MβLs), a dipyridyl-substituted thiosemicarbazone (DpC), was identified to be the broad-spectrum inhibitor of MβLs (NDM-1, VIM-2, IMP-1, ImiS, L1), with an IC value in the range of 0.021-1.08 µM. It reversibly and competitively inhibited NDM-1 with a K value of 10.2 nM. DpC showed broad-spectrum antibacterial effect on clinical isolate K. pneumonia, CRE, VRE, CRPA and MRSA, with MIC value ranged from 16 to 32 µg/mL, and exhibited synergistic antibacterial effect with meropenem on MβLs-producing bacteria, resulting in a 2-16-, 2-8-, and 8-fold reduction in MIC of meropenem against EC-MβLs, EC01-EC24, K. pneumonia, respectively. Moreover, mice experiments showed that DpC also had synergistic antibacterial action with meropenem. In this work, DpC was identified to be a potent scaffold for the development of broad-spectrum inhibitors of MβLs.
为了对抗金属β-内酰胺酶（MβLs）引起的超级细菌感染，我们鉴定出一种双吡啶取代的硫代缩氨基脲（DpC），它是 MβLs（NDM-1、VIM-2、IMP-1、ImiS、L1）的广谱抑制剂，其 IC 值在 0.021-1.08µM 范围内。它以 10.2nM 的 K 值可逆且竞争性地抑制 NDM-1。DpC 对临床分离的肺炎克雷伯菌、CRE、VRE、CRPA 和 MRSA 具有广谱的抗菌作用，其 MIC 值范围为 16 至 32µg/mL，与美罗培南联合使用对产 MβLs 的细菌具有协同抗菌作用，使美罗培南对 EC-MβLs、EC01-EC24、肺炎克雷伯菌的 MIC 值分别降低了 2-16 倍、2-8 倍和 8 倍。此外，小鼠实验表明，DpC 与美罗培南也具有协同抗菌作用。在这项工作中，DpC 被鉴定为开发 MβLs 广谱抑制剂的有效支架。
