New Potent Sulfonamide-Based Inhibitors of S. aureus Biotin Protein Ligase

The key regulatory metabolic enzyme, biotin protein ligase (BPL), is an attractive target for the development of novel antibiotics against multi-drug-resistant bacteria, such as Staphylococcus aureus. Here we report the synthesis and assay of a new series of inhibitors (6-9) against S. aureus BPL (SaBPL), where a component sulfonamide linker was used to mimic the acyl-phosphate group of the natural intermediate biotinyl-5 '-AMP (1). A pivotal correlation between the acidity of the central NH of the sulfonamide linker of 6-9 and in vitro inhibitory activity against SaBPL was observed. Specifically, sulfonylcarbamate 8, with its highly acidic sulfonyl central NH, as evaluated by H-1 NMR spectroscopy, showed exceptional potency (K-i = 10.3 +/- 3.8 nM). Furthermore, three inhibitors demonstrated minimum inhibitory concentrations of 16-32 mu g/mL against clinical methicillin-resistant S. aureus (MRSA) strains.