New Delhi metallo-β-lactamase-1 (NDM-1) is capable of hydrolyzing nearly all β-lactam antibiotics, posing an emerging threat to public health. There are currently less effective treatment options for treating NDM-1 positive “superbug”, and no promising NDM-1 inhibitors were used in clinical practice. In this study, structure–activity relationship based on thiosemicarbazone derivatives was systematically characterized and their potential activities combined with meropenem (MEM) were evaluated. Compounds 19bg and 19bh exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance. Further studies demonstrated compounds 19bg and 19bh were uncompetitive NDM-1 inhibitors with Ki = 0.63 and 0.44 μmol/L, respectively. Molecular docking speculated that compounds 19bg and 19bh were most likely to bind in the allosteric pocket which would affect the catalytic effect of NDM-1 on the substrate meropenem. Toxicity evaluation experiment showed that no hemolysis activities even at concentrations of 1000 mg/mL against red blood cells. In vivo experimental results showed combination of MEM and compound 19bh was markedly effective in treating infections caused by NDM-1 positive strain and prolonging the survival time of sepsis mice. Our finding showed that compound 19bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.

新德里金属-β-内酰胺酶-1 (NDM-1) 能够水解几乎所有的β-内酰胺类抗生素，对公众健康构成新的威胁。目前治疗 NDM-1 阳性“超级细菌”的疗效较差，临床实践中也没有使用有希望的 NDM-1 抑制剂。在这项研究中，系统地表征了基于氨基硫脲衍生物的构效关系，并评估了它们与美罗培南 (MEM) 结合的潜在活性。化合物19bg和19bh在逆转 MEM 耐药性方面表现出对 10 个 NDM 阳性分离临床分离株的优异活性。进一步的研究表明化合物19bg和19bh分别是K i = 0.63 和 0.44 μmol/L的非竞争性 NDM-1 抑制剂。分子对接推测化合物19bg和19bh最有可能结合在变构袋中，这会影响NDM-1对底物美罗培南的催化作用。毒性评价实验表明，即使在1000 mg/mL的浓度下对红细胞也没有溶血活性。体内实验结果表明，MEM与化合物19bh联合治疗NDM-1阳性株引起的感染，延长脓毒症小鼠的存活时间有显着疗效。我们的发现表明化合物19bh可能是开发新的抑制剂来治疗产生 NDM-1 的超级细菌的有希望的先导。