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

• Published in: ACS medicinal chemistry letters 2023-03, Vol.14 (3), p.285-290
• Main Authors: Stachura, Damian L., Nguyen, Stephanie, Polyak, Steven W., Jovcevski, Blagojce, Bruning, John B., Abell, Andrew D.
• Format: Article
• Language: English
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00505

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 K i values of 10 ± 2 and 30 ± 6 nM, respectively, against SaBPL. 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 SaBPL likely contributing to potent inhibition.