A template guided approach to generating cell permeable inhibitors of Staphylococcus aureus biotin protein ligase

作者：Paparella Ashleigh S; Feng Jiage; Blanco Rodriguez Beatriz; Feng Zikai; Phetsang Wanida; Blaskovich Mark A T; Cooper Matthew A; Booker Grant W; Polyak Steven W; Abell Andrew D^*

来源：Tetrahedron, 2018, 74(12): 1175-1183.

DOI：10.1016/j.tet.2017.10.032

• Enzyme inhibitors
• Antibiotic
• Biotin protein ligase
• Azide-alkyne cycloaddition
• Staphylococcus aureus

Inhibitors of biotin protein ligase (BPL) are novel antimicrobial compounds with the potential to treat infections caused by bacteria resistant to current antibiotics. A novel BPL inhibitor (12, K-i; 1.4 mu M) was synthesized from biotin acetylene and an azide-functionalized analogue of fluorescent nitrobenzofurazan by Cu(I) catalysed cycloaddition and also by template guided synthesis using wild-type BPL from Staphylococcus aureus. LC/HRMS-based detection provides improved sensitivity over previous reports using a mutant BPL, with demonstrated applicability to other BPLs. Super-imaging fluorescence microscopy demonstrated the accumulation of 12 in the cytoplasm of S. aureus, but not Escherichia coli. This novel fluorescent probe can be used to gain new insights into the mechanism of uptake, efflux and metabolism of BPL inhibitors in S. aureus.

• 出版日期2018-3-22