Discovery of thiosemicarbazone derivatives as effective New Delhi metallo-β-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates
10.1016/j.apsb.2020.07.005
- Author:
Bing ZHAO
1
;
Xinhui ZHANG
1
;
Tingting YU
1
;
Ying LIU
1
;
Xiaoling ZHANG
1
;
Yongfang YAO
1
;
Xuejian FENG
1
;
Hongmin LIU
1
;
Dequan YU
2
;
Liying MA
1
;
Shangshang QIN
1
Author Information
1. State Key Laboratory of Esophageal Cancer Prevention and Treament, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical Research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- Keywords:
(Boc)2O, di-tert-butyl decarbonate;
3-AP, 3-aminopyridine carboxaldehyde thiosemicarbazone;
AcOH, acetic acid;
Antibiotic resistance;
Boc, tert-butoxycarbonyl;
CLSI, Clinical and Laboratory Standards Institute;
DMAP, 4-dimethylaminopyridine;
DpC, di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone;
E. coli, Escherichia coli;
EDTA, ethylene diamine tetraacetic acid;
ESI, electrospray ionization;
HR-MS, high-resolution mass spectra;
IC50, half-maximal inhibitory concentrations;
Inhibitor;
K. pneumoniae, Klebsiella pneumoniae;
LQTS, long QT syndrome;
MBLs, metallo-β-lactamases class B;
MEM, meropenem;
MHA, Mueller-Hinton Agar;
MHB, Mueller-Hinton Broth;
MIC, minimum inhibitory concentration;
NDM-1, New Delhi metallo-β-lactamase-1;
New Delhi metallo-β-lactamase-1;
PBS, phosphate-buffered saline;
PK, pharmacokinetic;
RBCs, red blood cells;
SAR, structure–activity relationship;
THF, tetrahydrofuran;
TLC, thin layer chromatography;
TMS, tetramethylsilane;
Thiosemicarbazone derivatives;
UPLC, ultra-performance liquid chromatography;
conc. HCl, concentrated hydrochloric acid;
r.t., room temperature
- From:
Acta Pharmaceutica Sinica B
2021;11(1):203-221
- CountryChina
- Language:English
-
Abstract:
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.
