Discovery of thiosemicarbazone derivatives as effective New Delhi metallo-β-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates
New Delhi metallo-β-lactamase-1 (NDM-1) is capable of hydrolyzing nearly all β-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 clinica...
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| Main Authors: | , , , , , , , , , , |
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Elsevier,
2021-01-01T00:00:00Z.
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| 001 | doaj_8b2399cb7ac94e9d919b5377e17e0cde | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Bing Zhao |e author |
| 700 | 1 | 0 | |a Xinhui Zhang |e author |
| 700 | 1 | 0 | |a Tingting Yu |e author |
| 700 | 1 | 0 | |a Ying Liu |e author |
| 700 | 1 | 0 | |a Xiaoling Zhang |e author |
| 700 | 1 | 0 | |a Yongfang Yao |e author |
| 700 | 1 | 0 | |a Xuejian Feng |e author |
| 700 | 1 | 0 | |a Hongmin Liu |e author |
| 700 | 1 | 0 | |a Dequan Yu |e author |
| 700 | 1 | 0 | |a Liying Ma |e author |
| 700 | 1 | 0 | |a Shangshang Qin |e author |
| 245 | 0 | 0 | |a Discovery of thiosemicarbazone derivatives as effective New Delhi metallo-β-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates |
| 260 | |b Elsevier, |c 2021-01-01T00:00:00Z. | ||
| 500 | |a 2211-3835 | ||
| 500 | |a 10.1016/j.apsb.2020.07.005 | ||
| 520 | |a New Delhi metallo-β-lactamase-1 (NDM-1) is capable of hydrolyzing nearly all β-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 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 uncompetitive NDM-1 inhibitors with Ki = 0.63 and 0.44 μmol/L, respectively. Molecular docking speculated 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 experimental results showed combination of MEM and compound 19bh 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 19bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug. | ||
| 546 | |a EN | ||
| 690 | |a Thiosemicarbazone derivatives | ||
| 690 | |a New Delhi metallo-β-lactamase-1 | ||
| 690 | |a Inhibitor | ||
| 690 | |a Antibiotic resistance | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Acta Pharmaceutica Sinica B, Vol 11, Iss 1, Pp 203-221 (2021) | |
| 787 | 0 | |n http://www.sciencedirect.com/science/article/pii/S2211383520306316 | |
| 787 | 0 | |n https://doaj.org/toc/2211-3835 | |
| 856 | 4 | 1 | |u https://doaj.org/article/8b2399cb7ac94e9d919b5377e17e0cde |z Connect to this object online. |