Structural Study of Potent Triazole-Based Inhibitors of Staphylococcus aureus Biotin Protein Ligase

The rise of multidrug-resistant bacteria, such as Staphylococcus aureus, has highlighted global urgency for new classes of antibiotics. Biotin protein ligase (BPL), a critical metabolic regulatory enzyme, is an important target that shows significant promise in this context. Here we report the in silico docking, synthesis, and biological assay of a new series of N1- diphenylmethyl-1,2,3-triazole-based S. aureus BPL (SaBPL) inhibitors (8-19) designed to probe the adenine binding site and define whole-cell activity for this important class of inhibitor. Triazoles 13 and 14 with N1-propylamine and-butanamide substituents, respectively, were particularly potent with Ki values of 10 +/- 2 and 30 +/- 6 nM, respectively, against SaBPL. A strong correlation was apparent between the Ki values for 8-19 and the in silico docking, with hydrogen bonding to amino acid residues S128 and N212 of SaBPL likely contributing to potent inhibition.