Next Article in Journal
2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase
Next Article in Special Issue
Mutation S115T in IMP-Type Metallo-β-Lactamases Compensates for Decreased Expression Levels Caused by Mutation S119G
Previous Article in Journal
Lignin Accumulation in Three Pumelo Cultivars in Association with Sucrose and Energy Depletion
Previous Article in Special Issue
Nutrition Related Stress Factors Reduce the Transfer of Extended-Spectrum Beta-Lactamase Resistance Genes between an Escherichia coli Donor and a Salmonella Typhimurium Recipient In Vitro
Open AccessCommunication

Dithiocarbamate as a Valuable Scaffold for the Inhibition of Metallo-β-Lactmases

Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, the College of Chemistry and Materials Science, Northwest University, Xi’an 710127, China
*
Author to whom correspondence should be addressed.
Those authors contributed equally to this work.
Biomolecules 2019, 9(11), 699; https://doi.org/10.3390/biom9110699
Received: 11 October 2019 / Revised: 2 November 2019 / Accepted: 4 November 2019 / Published: 5 November 2019
(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)
The ‘superbug’ infection caused by metallo-β-lactamases (MβLs) has grown into an emergent health threat. Given the clinical importance of MβLs, a novel scaffold, dithiocarbamate, was constructed. The obtained molecules, DC1, DC8 and DC10, inhibited MβLs NDM-1, VIM-2, IMP-1, ImiS and L1 from all three subclasses, exhibiting an IC50 < 26 μM. DC1 was found to be the best inhibitor of ImiS (IC50 < 0.22 μM). DC1-2, DC4, DC8 and DC10 restored antimicrobial effects of cefazolin and imipenem against E. coli-BL21, producing NDM-1, ImiS or L1, and DC1 showed the best inhibition of E. coli cells, expressing the three MβLs, resulting in a 2-16-fold reduction in the minimum inhibitory concentrations (MICs) of both antibiotics. Kinetics and isothermal titration calorimetry (ITC) assays showed that DC1 exhibited a reversible, and partially mixed inhibition, of NDM-1, ImiS and L1, with Ki values of 0.29, 0.14 and 5.06 µM, respectively. Docking studies suggest that the hydroxyl and carbonyl groups of DC1 form coordinate bonds with the Zn (II) ions, in the active center of NDM-1, ImiS and L1, thereby inhibiting the activity of the enzymes. Cytotoxicity assays showed that DC1, DC3, DC7 and DC9 have low toxicity in L929 mouse fibroblastic cells, at a dose of up to 250 μM. These studies revealed that the dithiocarbamate is a valuable scaffold for the development of MβLs inhibitors. View Full-Text
Keywords: antibiotic resistance; metallo-β-lactamase; inhibitor; dithiocarbamate; activity assay antibiotic resistance; metallo-β-lactamase; inhibitor; dithiocarbamate; activity assay
Show Figures

Figure 1

MDPI and ACS Style

Ge, Y.; Xu, L.-W.; Liu, Y.; Sun, L.-Y.; Gao, H.; Li, J.-Q.; Yang, K. Dithiocarbamate as a Valuable Scaffold for the Inhibition of Metallo-β-Lactmases. Biomolecules 2019, 9, 699.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop