(-)-Epicatechin gallate serves as a novel new delhi metallo-β-lactamase-1(NDM-1)inhibitor

一种新型NDM-1抑制剂:(–)-表儿茶素没食子酸酯

Theβ-lactam antibiotic resistance caused by NDM-1 has become a major crisis of global public health.We have previously screened out(-)-epicatechin gallate(ECG)as a potent NDM-1 inhibitor.We further discussed its inhibitory effect and action mode in the present study.According to our results,ECG reversibly inactivated NDM-1 in a non-competitive mode,with an IC50 value of 4.48μM.ECG effectively recovered the activity of severalβ-lactam antibiotics against resistant strain harboring blaNDM-1.Especially,the effects on carbapenems were worth mentioning.The zinc supplement assay indicated a zinc-related mechanism of ECG.Different from traditional chelating agents,it showed low toxicity both in vivo and in vitro.In a word,our findings provided a promising NDM-1 inhibitor,ECG,which was able to assist carbapenems against NDM-1-producing strain.

NDM-1导致的β-内酰胺类抗生素耐药问题已成为威胁全球公共卫生的重大危机。我们前期经筛选发现(–)-表儿茶素没食子酸酯是一种有效的NDM-1抑制剂,本文进一步探讨了其抑制活性和作用方式。结果显示,(–)-表儿茶素没食子酸酯以一种可逆的、非竞争性的模式抑制NDM-1的活性,IC_(50)值为4.48μM。(–)-表儿茶素没食子酸酯能有效恢复多种β-内酰胺类抗生素对NDM-1菌的抑菌活性,特别是对于碳青霉烯类抗生素有较显著的作用。锌离子回补实验结果提示,(–)-表儿茶素没食子酸酯发挥作用可能与对锌离子的影响有关,然而不同于传统螯合剂,它在体内外均展现出较低的毒性。综上所述,我们的结果显示(–)-表儿茶素没食子酸酯能够协助碳青霉烯类抗生素抑制NDM-1产生菌,是一种具有潜力的NDM-1抑制剂。