NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors
Albert H. Chan, Sung Wook Yi, Ethan M. Weiner, Brendan R. Amer, Christopher K. Sue, Jeff Wereszczynski, Carly A. Dillen, Silvia Senese, Jorge Z. Torres, J. Andrew McCammon, Lloyd S. Miller, Michael E. Jung and Robert T. Clubb
Version of Record online: 6 MAR 2017 | DOI: 10.1111/cbdd.12962
NMR spectroscopy was used to determine the structure of Staphylococcus aureus sortase A transpeptidase enzyme in complex with a pyridazinone-based small molecule, a potential anti-infective agent. Computational and synthetic chemistry methods led to second-generation analogs that are 70-fold more potent than the lead molecule, less cytotoxic and effective at impairing sortase A-mediated protein display on the surface of S. aureus. These pyridazinone analogues are attractive candidates for further development into anti-infective agents.