Integrating Siderophore Substructures in Thiol-Based Metallo-β-Lactamase Inhibitors.

ABSTRACT: Metallo beta lactamases (MBLs) are among the most problematic resistance mechanisms of multidrug-resistant Gram-negative pathogens due to their broad substrate spectrum and lack of approved inhibitors. In this study, we propose the integration of catechol substructures into the design of thiol-based MBL inhibitors, aiming at mimicking bacterial siderophores for the active uptake by the iron acquisition system of bacteria. We synthesised two catechol-containing MBL inhibitors, as well as their dimethoxy counterparts, and tested them for in vitro inhibitory activity against NDM-1, VIM-1, and IMP-7. We demonstrated that the most potent catechol-containing MBL inhibitor is able to bind Fe³⁺ ions. Finally, we could show that this compound restores the antibiotic activity of imipenem

SUBMITTER: Rotter MJ 

PROVIDER: S-EPMC9962638 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature