4.7 Article

1,2-Isoselenazol-3(2H)-one derivatives as NDM-1 inhibitors displaying synergistic antimicrobial effects with meropenem on NDM-1 producing clinical isolates

Journal

BIOORGANIC CHEMISTRY
Volume 129, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.106153

Keywords

Carbapenem-resistant Enterobacteriaceae; NDM-1 inhibitors; Ebselen derivatives; Structure-based drug design; Synergistic activity

Funding

  1. National Natural Science Foundation of China [NSFC 81973170]
  2. Research Impact Fund of the Hong Kong Research Grant Council [R5011-18F]

Ask authors/readers for more resources

This study designed and developed a novel scaffold of benzo[d][1,2]selenazol-3(2H)-one derivatives, and the representative compound 15l showed strong antibacterial activity when combined with meropenem, with the potential to restore the antibacterial effect against clinically resistant Enterobacteriaceae strains.
The New Delhi beta-Lactamase 1 (NDM-1), one of the most prevalent types of metallo-beta-lactamases, has attracted extensive attention since its discovery. Extensive efforts have been made to develop inhibitor of NDM-1, how-ever, no inhibitor is available clinically so far. It is reported that Benzo[d][1,2]selenazol-3(2H)-one derivatives as covalent NDM-1 inhibitors can restore the efficacy of meropenem against NDM-1producing strains. In this study, 38 novel benzo or pyrido[d][1,2]selenazol-3(2H)-one derivatives were designed based on NDM-1 protein structure and structure-activity relationships study. Representative compound 15l exhibits significant synergistic antibacterial activity with meropenem against NDM-1 producing carbapenem-resistant Enterobacteriaceae (CRE) isolates, especially clinical CRE isolates (FIC indices ranging from 0.0625 to 0.25). ESI-MS analysis demonstrats that 15l covalently binds to NDM-1 enzyme, and the IC50 is 11.25 mu M. In conclusion, this study has developed a novel scaffold with higher activity to enrich the structural types of benzo[d][1,2]selenazol-3(2H)-one de-rivatives. Compound 15l can be considered as a promising lead compound to restore the antibacterial effect of meropenem in combating life-threatening CRE.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available