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Authors: Barthels, Fabian
Marincola, Gabriella
Marciniak, Tessa
Konhäuser, Matthias
Hammerschmidt, Stefan
Bierlmeier, Jan
Distler, Ute
Wich, Peter R.
Tenzer, Stefan
Schwarzer, Dirk
Ziebuhr, Wilma
Schirmeister, Tanja
Title: Asymmetric disulfanylbenzamides as irreversible and selective inhibitors of Staphylococcus aureus sortase A
Online publication date: 13-Aug-2021
Language: english
Abstract: 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 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.
DDC: 570 Biowissenschaften
570 Life sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY-NC-ND
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Journal: ChemMedChem
Pages or article number: 839
Publisher: Wiley-VCH
Publisher place: Weinheim u.a.
Issue date: 2020
ISSN: 1860-7187
Publisher URL:
Publisher DOI: 10.1002/cmdc.201900687
Appears in collections:JGU-Publikationen

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