Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-214581
- Staphylococcus aureus is one of the most frequent causes of nosocomial and community‐acquired infections, with drug‐resistant strains being responsible for tens of thousands of deaths per year. S. aureus sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active‐site cysteine. A broad series of derivatives were synthesized to derive structure‐activity relationships (SAR). In vitro and inStaphylococcus aureus is one of the most frequent causes of nosocomial and community‐acquired infections, with drug‐resistant strains being responsible for tens of thousands of deaths per year. S. aureus sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active‐site cysteine. A broad series of derivatives were synthesized to derive structure‐activity relationships (SAR). In vitro and in silico methods allowed the experimentally observed binding affinities and selectivities to be rationalized. The most active compounds were found to have single‐digit micromolar Ki values and caused up to a 66 % reduction of S. aureus fibrinogen attachment at an effective inhibitor concentration of 10 μM. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase‐mediated adherence of S. aureus cells.…
Autor(en): | Fabian Barthels, Gabriella Marincola, Tessa Marciniak, Matthias Konhäuser, Stefan Hammerschmidt, Jan Bierlmeier, Ute Distler, Peter R. Wich, Stefan Tenzer, Dirk Schwarzer, Wilma Ziebuhr, Tanja Schirmeister |
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URN: | urn:nbn:de:bvb:20-opus-214581 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Institut für Molekulare Infektionsbiologie |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | ChemMedChem |
Erscheinungsjahr: | 2020 |
Band / Jahrgang: | 15 |
Heft / Ausgabe: | 10 |
Erste Seite: | 839 |
Letzte Seite: | 850 |
Originalveröffentlichung / Quelle: | ChemMedChem 2020, 15(10):839–850. DOI: 10.1002/cmdc.201900687 |
DOI: | https://doi.org/10.1002/cmdc.201900687 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Freie Schlagwort(e): | antibiotics; biofilm; drug design; sortase A |
Datum der Freischaltung: | 30.06.2021 |
Lizenz (Deutsch): | CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International |