Structural Study of Potent Triazole-Based Inhibitors of <i>Staphylococcus aureus</i> Biotin Protein Ligase
Date
2023
Authors
Stachura, D.L.
Nguyen, S.
Polyak, S.W.
Jovcevski, B.
Bruning, J.B.
Abell, A.D.
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Journal article
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ACS Medicinal Chemistry Letters, 2023; 14(3):285-290
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Abstract
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.
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Data source: Supporting information, https://doi.org/10.1021/acsmedchemlett.2c00505
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Copyright 2023 American Chemical Society