Discovery of thiosemicarbazone derivatives as effective New Delhi metallo-β-lactamase-1(NDM-1)inhibitors against NDM-1 producing clinical isolates

• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（1）
• 所属期刊栏目: Original articles
• 页码范围: 203-221
• 页数: 19页
• 语种: 英文

摘要

New Delhi metallo-p-lactamase-1(NDM-1)is capable of hydrolyzing nearly all p-lactam an-tibiotics,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 prac-tice.In this study,structure—activity relationship based on thiosemicarbazone derivatives was systematically characterized and their potential activities combined with meropenem(MEM)were eval-uated.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 un-competitive NDM-1 inhibitors with Kr = 0.63 and 0.44 pmol/L,respectively.Molecular docking spec-ulated 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 exper-imental results showed combination of MEM and compound 19bh was markedly effective in treating in-fections 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 pro-ducing superbug.