A Degradation Product from Hydrolysate of Imipenem with Imis Broad-Spectrum Inhibits Metallo-β-Lactamases
| Author | Ying Ge | en |
| Author | Li-Wei Xu | en |
| Author | Jian-Bin Zhen | en |
| Author | Cheng Chen | en |
| Author | Miao Lv | en |
| Author | Jian-Peng Su | en |
| Author | Ke-Wu Yang | en |
| Author | Chengcheng Liu | en |
| Issued Date | 2020-10-31 | en |
| Abstract | Background: Infections caused by metallo-β-lactamases (MβLs)-producing antibiotic-resistant bacteria pose a severe threat to public health. The synergistic use of current antibiotics in combination with MβL inhibitors is a promising therapeutic mode against these antibiotic-resistant bacteria. Objectives: The study aimed to probe the inhibition of MβLs and obtain the active component, P1, in the degradation product after imipenem was hydrolyzed by ImiS. Methods: The hydrolysis of two carbapenems with MβL ImiS was monitored by UV-Vis in real-time, and the degradation product from the leaving group produced after imipenem was hydrolyzed (but not for faropenem) was purified by HPLC to give one component, P1. Results: Kinetic assays revealed that P1 exhibited a broad-spectrum inhibition against VIM-2, NDM-1, ImiS, and L1, from three sub-classes of MβLs, with IC50 values of 8 - 32, 13.8 - 29.3, and 14.2 - 19.2 µM, using imipenem, cefazolin, and nitrocefin as substrates, respectively. Also, P1 showed synergistic antibacterial efficacy against drug-resistant Escherichia coli producing VIM-2, NDM-1, ImiS, and L1, in combination with antibiotics, restoring 16 to 32-fold and 32 to 128-fold efficacies of imipenem and cefazolin, respectively. Spectroscopic and Ellman's reagent analyses suggested that P1, a mercaptoethyl-form imidamide, is a mechanism-based inhibitor, while faropenem has no substrate inhibition, due to the lack of a leaving group. Conclusions: This work reveals that the hydrolysate of imipenem, a carbapenem with a good leaving group, can be used in screening for broad-spectrum inhibitors of MβLs. | en |
| DOI | https://doi.org/10.5812/jjm.108141 | en |
| Keyword | Antibiotic Resistance | en |
| Keyword | Metallo-β-lactamase | en |
| Keyword | Inhibitor | en |
| Keyword | Synergistic Antibacterial Efficacy | en |
| Publisher | Brieflands | en |
| Title | A Degradation Product from Hydrolysate of Imipenem with Imis Broad-Spectrum Inhibits Metallo-β-Lactamases | en |
| Type | Research Article | en |