期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 2, 页码 214-221出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.10.074
关键词
Metallo-beta-lactamase; NDM-1 inhibitor; Cyclic dithiocarbamate; Antibiotic resistance
资金
- NSFC - China [U1204206, 81501782, 21702190]
- 863 Program - China [2015AA020911]
- Henan Province - China [17A350004, 152300410034]
The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the beta-lactam antibiotics, the metallo-beta-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 mu g/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 mu M. 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. (C) 2017 Elsevier Ltd. All rights reserved.
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