Discovery of thiosemicarbazone derivatives as effective New Delhi metallo-β-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates
| Autor: | Xin-Hui Zhang, Hong-Min Liu, Yongfang Yao, Li-Ying Ma, Xue-Jian Feng, Qin Shangshang, Tingting Yu, Bing Zhao, De-Quan Yu, Xiaoling Zhang, Ying Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
MEM
meropenem TMS tetramethylsilane Antibiotic resistance Antibiotics LQTS long QT syndrome conc. HCl concentrated hydrochloric acid Boc tert-butoxycarbonyl EDTA ethylene diamine tetraacetic acid 0302 clinical medicine Thiosemicarbazone derivatives DMAP 4-dimethylaminopyridine General Pharmacology Toxicology and Pharmaceutics MBLs metallo-β-lactamases class B (Boc)2O di-tert-butyl decarbonate 0303 health sciences ESI electrospray ionization Chemistry E. coli Escherichia coli Hemolysis 030220 oncology & carcinogenesis Toxicity Original Article DpC di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone NDM-1 New Delhi metallo-β-lactamase-1 THF tetrahydrofuran medicine.drug Inhibitor MIC minimum inhibitory concentration medicine.drug_class Allosteric regulation PBS phosphate-buffered saline New Delhi metallo-β-lactamase-1 K. pneumoniae Klebsiella pneumoniae IC50 half-maximal inhibitory concentrations PK pharmacokinetic Meropenem MHA Mueller-Hinton Agar UPLC ultra-performance liquid chromatography Microbiology Sepsis MHB Mueller-Hinton Broth 03 medical and health sciences Minimum inhibitory concentration AcOH acetic acid SAR structure–activity relationship medicine 030304 developmental biology TLC thin layer chromatography lcsh:RM1-950 CLSI Clinical and Laboratory Standards Institute medicine.disease r.t. room temperature HR-MS high-resolution mass spectra lcsh:Therapeutics. Pharmacology RBCs red blood cells 3-AP 3-aminopyridine carboxaldehyde thiosemicarbazone |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 11, Iss 1, Pp 203-221 (2021) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| Popis: | 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. Graphical abstract Structure–activity relationship based on thiosemicarbazone derivatives was systematically characterized. Compound 19bh exhibited excellent activity against 10 New Delhi metallo-β-lactamase-1 (NDM-1) producing clinical isolates in reversing meropenem resistance in vitro. Combination of meropenem and 19bh was markedly effective in treating infections caused by NDM-1 positive strain and prolonging the survival time of sepsis mice.Image 1 |
| Databáze: | OpenAIRE |
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