New Delhi metallo-b-lactmase-1（NDM-1） catalyzes the hydrolysis of b-lactam antibiotics and cleaves the b-lactam ring of the molecule, conferring bacterial resistance against these medicines. In an effort to discover...New Delhi metallo-b-lactmase-1（NDM-1） catalyzes the hydrolysis of b-lactam antibiotics and cleaves the b-lactam ring of the molecule, conferring bacterial resistance against these medicines. In an effort to discover novel agents to treat this superbug, an old drug methisazone was found to be a weak NDM-1 inhibitor, with an IC50 of 297.6 mmol/L. Based on this result, a series of isatin-β-thiosemicarbazones（IBTs）were synthesized and biologically evaluated as novel NDM-1 inhibitors. Nine of the IBT compounds showed IC50 values of 〈10 mmol/L, the best of which was 2.72 mmol/L. Comparative field analysis（Co MFA） contour maps were generated to depict the structural features and molecular docking was performed to understand the possible binding mode of these inhibitors. The present research hereby has provided valuable information for further discovery of NDM-1 inhibitors.展开更多
New Delhi metallo-b-lactamase-1(NDM-1)is capable of hydrolyzing nearly allβ-lactam antibiotics,posing an emerging threat to public health.There are currently less effective treatment options for treating NDM-1 positi...New Delhi metallo-b-lactamase-1(NDM-1)is capable of hydrolyzing nearly allβ-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 eactivity relationship based on thiosemicarbazone derivatives wassystematically characterized and their potential activities combined with meropenem(MEM)were evaluated.Compounds 19 bg and 19 bh exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance.Further studies demonstrated compounds 19 bg and 19 bh were uncompetitive NDM-1 inhibitors with Ki Z 0.63 and 0.44 mmol/L,respectively.Molecular docking speculated that compounds 19 bg and 19 bh 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/m L against red blood cells.In vivo experimental results showed combination of MEM and compound 19 bh 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 19 bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.展开更多
基金supported by the “111” Project of Ministry of Education of China (No. B06005)the National Natural Science Foundation of China (No. 21672114)the National Basic Research Program of China (No. 2013CB734004)
文摘New Delhi metallo-b-lactmase-1（NDM-1） catalyzes the hydrolysis of b-lactam antibiotics and cleaves the b-lactam ring of the molecule, conferring bacterial resistance against these medicines. In an effort to discover novel agents to treat this superbug, an old drug methisazone was found to be a weak NDM-1 inhibitor, with an IC50 of 297.6 mmol/L. Based on this result, a series of isatin-β-thiosemicarbazones（IBTs）were synthesized and biologically evaluated as novel NDM-1 inhibitors. Nine of the IBT compounds showed IC50 values of 〈10 mmol/L, the best of which was 2.72 mmol/L. Comparative field analysis（Co MFA） contour maps were generated to depict the structural features and molecular docking was performed to understand the possible binding mode of these inhibitors. The present research hereby has provided valuable information for further discovery of NDM-1 inhibitors.
基金supported by National Natural Science Foundation of China(Grant Nos.81903447 for Bing Zhao,81903623 for Yongfang Yao,81703328 for Liying Ma,and 81430085 for Hongmin Liu)National Key Research and Development Project of China(Nos.2016YFA0501800 and 2018YFE0195100 for Hongmin Liu)
文摘New Delhi metallo-b-lactamase-1(NDM-1)is capable of hydrolyzing nearly allβ-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 eactivity relationship based on thiosemicarbazone derivatives wassystematically characterized and their potential activities combined with meropenem(MEM)were evaluated.Compounds 19 bg and 19 bh exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance.Further studies demonstrated compounds 19 bg and 19 bh were uncompetitive NDM-1 inhibitors with Ki Z 0.63 and 0.44 mmol/L,respectively.Molecular docking speculated that compounds 19 bg and 19 bh 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/m L against red blood cells.In vivo experimental results showed combination of MEM and compound 19 bh 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 19 bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.
