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Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A
Author(s) -
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
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900687
Subject(s) - staphylococcus aureus , sortase , sortase a , cysteine , chemistry , cytotoxicity , microbiology and biotechnology , virulence , in vitro , active site , biochemistry , stereochemistry , enzyme , biology , bacteria , gene , genetics
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 K i 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.