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 ( Sa BPL) 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 K i values of 10 ± 2 and 30 ± 6 nM, respectively, against Sa BPL. A strong correlation was apparent between the K i values for 8 - 19 and the in silico docking, with hydrogen bonding to amino acid residues S128 and N212 of Sa BPL likely contributing to potent inhibition.