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

New Delhi metallo--lactamase-1 (NDM-1) is capable of hydrolyzing nearly all -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 and exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance. Further studies demonstrated compounds and were uncompetitive NDM-1 inhibitors with i = 0.63 and 0.44 μmol/L, respectively. Molecular docking speculated that compounds and 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. experimental results showed combination of MEM and compound 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 might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.