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

Damian L Stachura; Stephanie Nguyen; Steven W Polyak; Blagojce Jovcevski; John B Bruning; Andrew D Abell

doi:10.1021/acsmedchemlett.2c00505

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

ACS Med Chem Lett. 2023 Feb 21;14(3):285-290. doi: 10.1021/acsmedchemlett.2c00505. eCollection 2023 Mar 9.

Authors

Damian L Stachura^{1

1}, Stephanie Nguyen², Steven W Polyak³, Blagojce Jovcevski^{1

1}, John B Bruning², Andrew D Abell^{1

1}

Affiliations

¹ Department of Chemistry and Centre for Nanoscale BioPhotonics (CNBP) and Institute of Photonics and Advanced Sensing (IPAS), School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
² Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
³ UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5005, Australia.

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 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.