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 ( Sa BPL), 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 Sa BPL was observed. Specifically, sulfonylcarbamate 8 , with its highly acidic sulfonyl central NH, as evaluated by 1 H NMR spectroscopy, showed exceptional potency ( K i = 10.3 ± 3.8 nM). Furthermore, three inhibitors demonstrated minimum inhibitory concentrations of 16-32 μg/mL against clinical methicillin-resistant S . aureus (MRSA) strains.