S. aureus Sortase A inhibitors as anti-virulent biofilm modulators
Fabian Barthels, Stefan Hammerschmidt, Christian Kersten & AK Ziebuhr (Universität Würzburg)
The ongoing spread of antibiotic resistance among Gram-positive bacteria such as Staphylococcus aureus highlights the need for new treatment options beyond traditional antibiotics. In this respect, exploring virulence mechanisms as drug targets might provide novel opportunities to interfere with bacterial pathogenicity. We aim to design novel S. aureus sortase A inhibitors to interfere with virulence determinants.
Recently, we identified disulfanylbenzamides as a new class of potent inhibitors against sortase A acting by covalent modification of the active site cysteine. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase-mediated adherence of S. aureus cells. Biophysical investigations such as differential scanning fluorimetry and mass spectrometry allowed us to elucidate the covalent inhibition mode and to design a docking-supported model of ligand binding.
Barthels, F.; Marincola, G.; Marciniak, T.; Konhäuser, M.; Hammerschmidt, S.; Bierlmeier, J.; Distler, U.; Wich, P. R.; Tenzer, S.; Schwarzer, D.; Ziebuhr, W.; Schirmeister, T. Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus Aureus Sortase A. ChemMedChem 2020, 15, 10, 839–850.