2. Academic Validation
  3. Dithiocarbamates: Efficient metallo-β-lactamase inhibitors with good antibacterial activity when combined with meropenem

Dithiocarbamates: Efficient metallo-β-lactamase inhibitors with good antibacterial activity when combined with meropenem

  • Bioorg Med Chem Lett. 2018 Nov 15;28(21):3436-3440. doi: 10.1016/j.bmcl.2018.09.028.
Ming-Ming Wang 1,  Wen-Chao Chu 1,  Yi Yang 1,  Qian-Qian Yang 1,  Shang-Shang Qin 2,  En Zhang 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China.
  • 2 School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China.
  • 3 School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China. Electronic address: zhangen@zzu.edu.cn.
PMID: 30262427 DOI: 10.1016/j.bmcl.2018.09.028
Abstract

The activity of β-lactam Antibiotics is compromised by metallo-β-lactamases (MBLs). Herein, a series of dithiocarbamate derivatives were designed and synthesized. Their Antibacterial activities were tested in combination with meropenem (MEM) against several MBL (NDM and IMP type)-producing clinical isolates. Clinical isolates harboring NDM-1 and IMP-4 became susceptible to MEM when it was combined with dithiocarbamate compounds 4a, 4b or 4f synthesized in this work. Compounds 4a and 4b increased the effectiveness of MEM by up to 2560 times against strains. In vitro bactericidal dynamics tests showed that bacteria died within 24 h when they were treated with compound 4f + MEM. Compounds 4a, 4b and 4f were non-hemolytic and exhibited low toxicity toward HeLa cells in vitro. These data show that compounds containing dithiocarbamate functional group may be helpful in the development of MBL inhibitors.

Keywords

Antibacterial activity; Antibiotic resistance; Dithiocarbamates; Meropenem; Metallo-β-lactamase inhibitors.

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