NOTA analogue: A first dithiocarbamate inhibitor of metallo-ß-lactamases.

The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the ß-lactam antibiotics, the metallo-ß-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 ±â€¯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.

H2depda: An acyclic adjuvant potentiates meropenem activity in vitro against metallo-ß-lactamase-producing enterobacterales.

Metallo-ß-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) pose an emerging threat to public health worldwide. An effective inhibitor of MBLs is therefore urgently needed for clinical use. In this study, two acyclic pyridine-containing ligands, H2dedpa and compound 8, were discovered with excellent activities when combined with meropenem (MEM) against MBL (blaNDM and blaIMP)-producing clinical isolates, including Escherichia coli, Citrobacter freundii, Proteus mirabilis, Enterobacter cloacae and Klebsiella pneumoniae. In particular, these two compounds improved the activity of MEM against E. coli harboring the blaNDM-4 gene by nearly 40,960 times. H2dedpa (IC50 = 0.17 ±â€¯0.04 µM) and compound 8 (IC50 = 0.04 ±â€¯0.02 µM) showed higher inhibitory activity against blaNDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC50 = 28.84 ±â€¯0.70 µM). A sterilization kinetics experiment showed that H2dedpain combined with MEM could kill 99.9% of bacteria within 24 h H2dedpa and compound 8 are therefore promising MBL inhibitors.