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
Year of first publication:	2020
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
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-6261
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY-NC-ND
Information on rights of use:	https://creativecommons.org/licenses/by-nc-nd/4.0/
Journal:	ChemMedChem 15 10
Pages or article number:	839 850
Publisher:	Wiley-VCH
Publisher place:	Weinheim u.a.
Issue date:	2020
ISSN:	1860-7187
Publisher URL:	https://doi.org/10.1002/cmdc.201900687
Publisher DOI:	10.1002/cmdc.201900687
Appears in collections:	JGU-Publikationen