Stachura Damian L, Kalyvas John T, Abell Andrew D
Centre for Nanoscale BioPhotonics (CNBP) and Institute of Photonics and Advanced Sensing (IPAS), Department of Chemistry, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia.
ACS Med Chem Lett. 2024 Sep 3;15(9):1467-1473. doi: 10.1021/acsmedchemlett.4c00325. eCollection 2024 Sep 12.
The key regulatory metabolic enzyme, biotin protein ligase (BPL), is an attractive target for the development of novel antibiotics against multi-drug-resistant bacteria, such as . Here we report the synthesis and assay of a new series of inhibitors (-) against . BPL (BPL), where a component sulfonamide linker was used to mimic the acyl-phosphate group of the natural intermediate biotinyl-5'-AMP (). A pivotal correlation between the acidity of the central NH of the sulfonamide linker of - and inhibitory activity against BPL was observed. Specifically, sulfonylcarbamate , with its highly acidic sulfonyl central NH, as evaluated by H NMR spectroscopy, showed exceptional potency ( = 10.3 ± 3.8 nM). Furthermore, three inhibitors demonstrated minimum inhibitory concentrations of 16-32 μg/mL against clinical methicillin-resistant . (MRSA) strains.
关键的调节代谢酶，生物素蛋白连接酶（BPL），是开发针对多药耐药细菌（如……）的新型抗生素的一个有吸引力的靶点。在此，我们报告了一系列新的针对……的抑制剂（-）的合成及测定。BPL（BPL），其中一个磺酰胺连接基团被用于模拟天然中间体生物素 - 5'- 腺苷酸（……）的酰基磷酸基团。观察到 - 的磺酰胺连接基团中心NH的酸度与对BPL的抑制活性之间存在关键关联。具体而言，通过核磁共振氢谱（H NMR）光谱评估，具有高度酸性磺酰基中心NH的磺酰氨基甲酸酯……显示出卓越的效力（IC50 = 10.3 ± 3.8 nM）。此外，三种抑制剂对临床耐甲氧西林……（MRSA）菌株的最低抑菌浓度为16 - 32 μg/mL。
