Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A

• DOI: 10.1002/cmdc.201900687
• Publication Date: 2020-03-02T10:38:03Z
• Authors: 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
• Keywords: 0301 basic medicine; 570; Staphylococcus aureus; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; ddc:540; Microbial Sensitivity Tests; Full Papers; 540; Aminoacyltransferases; Anti-Bacterial Agents; 570 Life sciences; 3. Good health; Cysteine Endopeptidases; Structure-Activity Relationship; 03 medical and health sciences; Bacterial Proteins; 616; Benzamides; ddc:570; Enzyme Inhibitors; 570 Biowissenschaften

AbstractStaphylococcus 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.