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  • Title: Integrating Siderophore Substructures in Thiol-Based Metallo-β-Lactamase Inhibitors.
    Author: Rotter MJ, Zentgraf S, Weizel L, Frank D, Burgers LD, Brunst S, Fürst R, Proschak A, Wichelhaus TA, Proschak E.
    Journal: Molecules; 2023 Feb 20; 28(4):. PubMed ID: 36838971.
    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 in NDM-1-expressing K. pneumoniae, while leaving HUVEC cells completely unaffected. Thus, siderophore-containing MBL inhibitors might be a valuable strategy to overcome bacterial MBL-mediated resistance to beta lactam antibiotics.
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