a degradation product from hydrolysate of imipenem with imis broad-spectrum inhibits metallo-β-lactamases

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 subclasses 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.