NOTA analogue: A first dithiocarbamate inhibitor of metallo-β-lactamases

Abstract

The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the β-lactam antibiotics, the metallo-β-lactamases (MBLs) is one of the most important reasons. In this paper, a series of cyclic dithiocarbamate compounds were synthesized and their inhibition activities against MBLs were initially tested combined with meropenem (MEM) by in vitro antibacterial efficacy tests. Sodium 1,4,7-triazonane-1,4,7-tris(carboxylodithioate) (compound 5) was identified as the most active molecule to restore the activity of MEM. Further anti-bacterial effectiveness assessment, compound 5 restored the activity of MEM against Escherichia coli, Citrobacter freundii, Proteus mirabilis and Klebsiella pneumonia, which carried resistance genes of blaNDM-1. The compound 5 was non-hemolytic, even at a concentration of 1000 µg/mL. This compound was low toxic toward mammalian cells, which was confirmed by fluorescence microscopy image and the inhibition rate of HeLa cells. The Ki value of compounds 5 against NDM-1 MBL was 5.63 ± 1.27 μM. Zinc ion sensitivity experiments showed that the inhibitory effect of compound 5 as a MBLs inhibitor was influenced by zinc ion. The results of the bactericidal kinetics displayed that compound 5 as an adjuvant assisted MEM to kill all bacteria. These data validated that this NOTA dithiocarbamate analogue is a good inhibitor of MBLs.