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首页> 外文期刊>The Journal of biological chemistry >Selective inhibition of Biotin Protein Ligase from Staphylococcus aureus
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Selective inhibition of Biotin Protein Ligase from Staphylococcus aureus

机译：来自金黄色葡萄球菌的生物素蛋白连接酶的选择性抑制作用

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There is a well documented need to replenish the antibiotic pipeline with new agents to combat the rise of drug resistant bacteria. One strategy to combat resistance is to discover new chemical classes immune to current resistance mechanisms that inhibit essential metabolic enzymes. Many of the obvious drug targets that have no homologous isozyme in the human host have now been investigated. Bacterial drug targets that have a closely related human homologue represent a new frontier in antibiotic discovery. However, to avoid potential toxicity to the host, these inhibitors must have very high selectivity for the bacterial enzyme over the human homolog. We have demonstrated that the essential enzyme biotin protein ligase (BPL) from the clinically important pathogen Staphylococcus aureus could be selectively inhibited. Linking biotin to adenosine via a 1,2,3 triazole yielded the first BPL inhibitor selective for S. aureus BPL over the human equivalent. The synthesis of new biotin 1,2,3-triazole analogues using click chemistry yielded our most potent structure (Ki 90 nm) with a >1100-fold selectivity for the S. aureus BPL over the human homologue. X-ray crystallography confirmed the mechanism of inhibitor binding. Importantly, the inhibitor showed cytotoxicity against S. aureus but not cultured mammalian cells. The biotin 1,2,3-triazole provides a novel pharmacophore for future medicinal chemistry programs to develop this new antibiotic class.
机译：有一种有效的需要补充抗生素管道，并用新的药剂打击耐药细菌的兴起。一种对抗抵抗的一个策略是发现对抑制基本代谢酶的电流阻力机制的新化学类别。现在已经研究了人体宿主中没有同工同工学的许多明显的药物靶标。具有密切相关的人类同源物的细菌药物靶标在抗生素发现中代表了一种新的前沿。然而，为了避免对宿主的潜在毒性，这些抑制剂必须对人同源物的细菌酶具有非常高的选择性。我们已经证明，可以选择性地抑制来自临床重要病原体金黄色葡萄球菌的基本酶生物素蛋白质连接酶（BPL）。通过1,2,3三唑将生物素与腺苷连接到腺苷，从人类当量上产生了对S.UUREUS BPL的第一BPL抑制剂选择性。使用咔哒化学的新生物素1,2,3-三唑类似物的合成产生了我们最有效的结构（Ki 90nm），其对人类同源物的S. aureus BPL具有> 1100倍的选择性。 X射线晶体学证实了抑制剂结合的机制。重要的是，抑制剂显示出对金黄色葡萄球菌的细胞毒性，但不培养哺乳动物细胞。生物素1,2,3-三唑为未来的药物化学计划提供新的药仔植物，以发展这种新的抗生素类。

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