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

Autor: Marco J. Rotter, Sabrina Zentgraf, Lilia Weizel, Denia Frank, Luisa D. Burgers, Steffen Brunst, Robert Fürst, Anna Proschak, Thomas A. Wichelhaus, Ewgenij Proschak
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Molecules, Vol 28, Iss 4, p 1984 (2023)
Druh dokumentu: article
ISSN: 28041984
1420-3049
DOI: 10.3390/molecules28041984
Popis: 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.
Databáze: Directory of Open Access Journals
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