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

被引：1
|
作者：
Stachura, Damian L. [1 ,2 ,3 ]
Nguyen, Stephanie [4 ]
Polyak, Steven W. [5 ]
Jovcevski, Blagojce [1 ,2 ,3 ]
Bruning, John B. [4 ]
Abell, Andrew D. [1 ,2 ,3 ]
机构：
[1] Univ Adelaide, Dept Chem, Adelaide, SA 5005, Australia
[2] Univ Adelaide, Ctr Nanoscale BioPhoton CNBP, Adelaide, SA 5005, Australia
[3] Univ Adelaide, Inst Photon & Adv Sensing IPAS, Sch Biol Sci, Adelaide, SA 5005, Australia
[4] Univ Adelaide, Sch Biol Sci, Dept Mol & Cellular Biol, Adelaide, SA 5005, Australia
[5] Univ South Australia, UniSA Clin & Hlth Sci, Adelaide, SA 5005, Australia
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 03期
关键词：
Biotin protein ligase; Staphylococcus aureus; antibiotic; triazole; inhibitor; MECHANISMS;
D O I：
10.1021/acsmedchemlett.2c00505
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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.
引用
收藏
页码：285 / 290
页数：6
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