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The inhibition of the VIM-2 and IMP-1 METALLO-β-LACTAMASES by cationic peptides
Get PDFMetallo-β-lactamases (MBLs) are major contributors to bacterial antibiotic resistance due to their
ability to cleave most β-lactam antibiotics. At the present time there are no clinically approved
inhibitors of MBLs. However, previous preliminary studies have demonstrated that cationic
peptides have the ability to inhibit these enzymes.
Herein, more thorough investigations into the structure-activity relationship between two
MBLs, VIM-2 and IMP-1, and cationic peptides are described, demonstrating that the inhibitory
potency of these peptides increased with the number of arginine residues (IC50 of 10 nM for the
most potent VIM-2 inhibitor). The degree of inhibition also varied depending on the β-lactam
substrate and the MBL employed. Furthermore, steady-state and stopped-flow
spectrophotometric studies demonstrated that the inhibition mediated by these peptides followed
a complex mode of inhibition. In addition, results from spectroscopic studies (including UV-Vis,
tryptophan fluorescence and dynamic light scattering) showed that the inhibition of MBLs by
cationic peptides results in partially reversible peptide-influenced MBL aggregation. The better
understanding of the relationship between these peptides and MBLs may lead to the development
of novel MBL inhibitors suitable for clinical use
