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doi:10.22028/D291-39050
Title: | N-Aryl Mercaptopropionamides as Broad-Spectrum Inhibitors of Metallo-β-Lactamases |
Author(s): | Kaya, Cansu Konstantinović, Jelena Kany, Andreas M. Andreas, Anastasia Kramer, Jan S. Brunst, Steffen Weizel, Lilia Rotter, Marco J. Frank, Denia Yahiaoui, Samir Müller, Rolf Hartmann, Rolf W. Haupenthal, Jörg Proschak, Ewgenij Wichelhaus, Thomas A. Hirsch, Anna K. H. |
Language: | English |
Title: | Journal of Medicinal Chemistry |
Volume: | 65 |
Issue: | 5 |
Pages: | 3913-3922 |
Publisher/Platform: | American Chemical Society |
Year of Publication: | 2022 |
DDC notations: | 500 Science |
Publikation type: | Journal Article |
Abstract: | Drug-resistant pathogens pose a global challenge to public health as they cause diseases that are extremely difficult to cure. Metallo-β-lactamases (MBLs) are a diverse set of zinc-containing enzymes that catalyze the hydrolysis of β-lactam drugs, including carbapenems, which are considered as the last resort to fight severe infections. To restore the activity of current β-lactam antibiotics and to offer an orthogonal strategy to the discovery of new antibiotics, we have identified a series of polar N-aryl mercaptopropionamide derivatives as potent inhibitors of several class B1 MBLs. We have identified a hit structure with high selectivity restoring the effect of imipenem and reducing minimum inhibitory concentration (MIC) values up to 256-fold in resistant isolates from Escherichia coli. Furthermore, the combination of imipenem with our inhibitor showed in vivo efficacy in a Galleria mellonella model, increasing the survival rate of infected larvae by up to 31%. |
DOI of the first publication: | 10.1021/acs.jmedchem.1c01755 |
URL of the first publication: | https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01755 |
Link to this record: | urn:nbn:de:bsz:291--ds-390509 hdl:20.500.11880/35218 http://dx.doi.org/10.22028/D291-39050 |
ISSN: | 1520-4804 0022-2623 |
Date of registration: | 16-Feb-2023 |
Description of the related object: | Supporting Information |
Related object: | https://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.1c01755/suppl_file/jm1c01755_si_001.pdf https://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.1c01755/suppl_file/jm1c01755_si_002.csv |
Faculty: | NT - Naturwissenschaftlich- Technische Fakultät |
Department: | NT - Pharmazie |
Professorship: | NT - Prof. Dr. Rolf W. Hartmann NT - Prof. Dr. Anna Hirsch NT - Prof. Dr. Rolf Müller |
Collections: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
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