Improved mutasynthetic approaches for the production of modified aminocoumarin antibiotics
Improved mutasynthetic approaches for the production of modified aminocoumarin antibiotics
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DOI：
10.1016/j.chembiol.2007.07.014
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发表时间：
2007-08-01
影响因子：
--
通讯作者：
Heide, Lutz
中科院分区：
文献类型：
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作者：
Anderle, Christine;Hennig, Susanne;Heide, Lutz
本研究报告了氨基香豆素类抗生素生产的改进突变合成方法。以前，具有不同取代的苯甲酰基部分的anninocounnarins的突变合成生产受到酰胺合成酶CloL的底物特异性的限制。我们表达了两个酰胺合成酶与不同的底物特异性，CouL和SimL，在适当的工程生产菌株。在不被CloL接受但被SimL或CouL接受的前体类似物进料后，产生并以制备量分离了一系列在我们先前的实验中无法获得的氨基香豆素。此外，我们开发了一个两阶段的突变合成程序的杂交抗生素的生产，显示的取代模式的新生霉素的anninocournarin部分和氯霉素的脱氧糖部分。苯甲酰基部分的取代模式通过外部添加适当的前体来确定。利用这些方法合成了25个氨基香豆素类化合物，并通过质谱和核磁共振氢谱对其结构进行了鉴定。
This study reports improved mutasynthetic approaches for the production of aminocoumarin antibiotics. Previously, the mutasynthetic production of anninocounnarins with differently substituted benzoyl moieties was limited by the substrate specificity of the amide synthetase CloL. We expressed two amide synthetases with different substrate specificity, CouL and SimL, in appropriately engineered producer strains. After feeding of precursor analogs that were not accepted by CloL, but by SimL or CouL, a range of aminocournarins, unattainable in our previous experiments, was produced and isolated in preparative amounts. Further, we developed a two-stage mutasynthesis procedure for the production of hybrid antibiotics that showed the substitution pattern of novobiocin in the anninocournarin moiety and that of clorobiocin in the deoxysugar moiety. The substitution pattern of the benzoyl moiety was determined by external addition of an appropriate precursor. Twenty-five aminocoumarin compounds were prepared by these methods, and their structures were elucidated with mass and H-1-NMR spectroscopy.