Structural Study of Potent Triazole-Based Inhibitors of Biotin Protein Ligase.

The rise of multidrug-resistant bacteria, such as , 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 docking, synthesis, and biological assay of a new series of -diphenylmethyl-1,2,3-triazole-based BPL (BPL) inhibitors (-) designed to probe the adenine binding site and define whole-cell activity for this important class of inhibitor. Triazoles and with -propylamine and -butanamide substituents, respectively, were particularly potent with values of 10 ± 2 and 30 ± 6 nM, respectively, against BPL. A strong correlation was apparent between the values for - and the docking, with hydrogen bonding to amino acid residues S128 and N212 of BPL likely contributing to potent inhibition.