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