Year: 2014
Type: dissertation
Abstract: Metallo-β-lactamases (MBLs) are major contributors to bacterial antibiotic resistance due to their \nability to cleave most β-lactam antibiotics. At the present time there are no clinically approved \ninhibitors of MBLs. However, previous preliminary studies have demonstrated that cationic \npeptides have the ability to inhibit these enzymes. \nHerein, more thorough investigations into the structure-activity relationship between two \nMBLs, VIM-2 and IMP-1, and cationic peptides are described, demonstrating that the inhibitory \npotency of these peptides increased with the number of arginine residues (IC50 of 10 nM for the \nmost potent VIM-2 inhibitor). The degree of inhibition also varied depending on the β-lactam \nsubstrate and the MBL employed. Furthermore, steady-state and stopped-flow \nspectrophotometric studies demonstrated that the inhibition mediated by these peptides followed \na complex mode of inhibition. In addition, results from spectroscopic studies (including UV-Vis, \ntryptophan fluorescence and dynamic light scattering) showed that the inhibition of MBLs by \ncationic peptides results in partially reversible peptide-influenced MBL aggregation. The better \nunderstanding of the relationship between these peptides and MBLs may lead to the development \nof novel MBL inhibitors suitable for clinical use.
Author: Caitlyn M. Rotondo
Language: English
Subfield: Microbiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1949540501