NOTA analogue: A first dithiocarbamate inhibitor of metallo-beta-lactamases
NOTA analogue: A first dithiocarbamate inhibitor of metallo-beta-lactamases
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NOTA 类似物：第一个金属-β-内酰胺酶二硫代氨基甲酸盐抑制剂
DOI：
10.1016/j.bmcl.2017.10.074
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发表时间：
2018
影响因子：
2.7
通讯作者：
Qin Shangshang
中科院分区：
文献类型：
--
作者：
Zhang En;Wang Ming-Ming;Huang Shu-Chao;Xu Shuai-Min;Cui De-Yun;Bo Yuan-Li;Bai Peng-Yan;Hua Yong-Gang;Xiao Chun-Ling;Qin Shangshang
抗生素药物（如碳青霉烯类）耐药性的出现正在成为一场全球危机。在β-内酰胺类抗生素的耐药因素中，金属-β-内酰胺酶(MBLs)是最重要的原因之一。本文合成了一系列环状二硫代氨基甲酸酯类化合物，并初步考察了其与美罗培南（MEM）联用的体外抑菌效果。 1,4,7-三氮烷-1,4,7-三(羧基二硫代)钠（化合物5）被确定为恢复MEM活性最活跃的分子。进一步抗菌效果评估，化合物5恢复了MEM对携带blaNDM-1耐药基因的大肠杆菌、弗氏柠檬酸杆菌、奇异变形杆菌和肺炎克雷伯菌的活性。即使浓度为 1000 µg/mL，化合物 5 也不会溶血。该化合物对哺乳动物细胞的毒性较低，荧光显微镜图像和HeLa细胞的抑制率证实了这一点。化合物5针对NDM-1 MBL的Ki值为5.63±1.27μM。锌离子敏感性实验表明，化合物5作为MBLs抑制剂的抑制作用受到锌离子的影响。杀菌动力学结果表明，化合物5作为佐剂辅助MEM杀死所有细菌。这些数据证实了这种 NOTA 二硫代氨基甲酸酯类似物是一种良好的 MBL 抑制剂。
The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the β-lactam antibiotics, the metallo-β-lactamases (MBLs) is one of the most important reasons. In this paper, a series of cyclic dithiocarbamate compounds were synthesized and their inhibition activities against MBLs were initially tested combined with meropenem (MEM) by in vitro antibacterial efficacy tests. Sodium 1,4,7-triazonane-1,4,7-tris(carboxylodithioate) (compound5) was identified as the most active molecule to restore the activity of MEM. Further anti-bacterial effectiveness assessment, compound5restored the activity of MEM againstEscherichia coli, Citrobacter freundii, Proteus mirabilis and Klebsiella pneumonia, which carried resistance genes ofblaNDM-1. The compound5was non-hemolytic, even at a concentration of 1000 µg/mL. This compound was low toxic toward mammalian cells, which was confirmed by fluorescence microscopy image and the inhibition rate of HeLa cells. TheKivalue of compounds5against NDM-1 MBL was 5.63 ± 1.27 μM. Zinc ion sensitivity experiments showed that the inhibitory effect of compound5as a MBLs inhibitor was influenced by zinc ion. The results of the bactericidal kinetics displayed that compound5as an adjuvant assisted MEM to kill all bacteria. These data validated that this NOTA dithiocarbamate analogue is a good inhibitor of MBLs.