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

Abstract

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 1H 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.