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A template guided approach to generating cell permeable inhibitors of Staphylococcus aureus biotin protein ligase |
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| Authors: | Ashleigh S Paparella Jiage Feng Beatriz Blanco-Rodriguez Zikai Feng Wanida Phetsang Mark AT Blaskovich Matthew A Cooper Grant W Booker Steven W Polyak Andrew D Abell |
| Institution: | 1. School of Biological Sciences, University of Adelaide, South Australia, 5005, Australia;2. Department of Chemistry, University of Adelaide, South Australia, 5005, Australia;3. Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, South Australia 5005, Australia;4. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia |
| Abstract: | 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, Ki 1.4 μM) 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. |
| Keywords: | Enzyme inhibitors Antibiotic Biotin protein ligase Azide-alkyne cycloaddition Corresponding author Department of Chemistry University of Adelaide South Australia 5005 Australia |
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