New Potent Sulfonamide-Based Inhibitors of <i>S</i>. <i>aureus</i> 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 <i>Staphylococcus aureus</i>. Here we report the synthesis and assay of a new series of inhibitors (<b>6</b>-<b>9</b>) against <i>S</i>. <i>aureus</i> BPL (<i>Sa</i>BPL), where a component sulfonamide linker was used to mimic the acyl-phosphate group of the natural intermediate biotinyl-5'-AMP (<b>1</b>). A pivotal correlation between the acidity of the central NH of the sulfonamide linker of <b>6</b>-<b>9</b> and <i>in vitro</i> inhibitory activity against <i>Sa</i>BPL was observed. Specifically, sulfonylcarbamate <b>8</b>, with its highly acidic sulfonyl central NH, as evaluated by ¹H NMR spectroscopy, showed exceptional potency (<i>K</i> _i = 10.3 ± 3.8 nM). Furthermore, three inhibitors demonstrated minimum inhibitory concentrations of 16-32 μg/mL against clinical methicillin-resistant <i>S</i>. <i>aureus</i> (MRSA) strains.