Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives.
Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives.
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DOI：
10.1038/s41467-017-01659-1
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发表时间：
2017-11-28
影响因子：
16.6
通讯作者：
Foster GD
中科院分区：
文献类型：
--
作者：
Alberti F;Khairudin K;Venegas ER;Davies JA;Hayes PM;Willis CL;Bailey AM;Foster GD
抗生素耐药性的上升是人类健康的主要威胁。担子菌类真菌代表了一种未开发的抗微生物剂来源，截短侧耳素是由Clitopilus passeckerianus产生的一种二萜，是这些真菌中唯一的抗生素，导致商业衍生物。在这里，我们报告了截短侧耳素生物合成中所涉及的步骤的遗传特征，通过合理的异源表达，在Aspergilluslaugha中，再加上分离和详细的结构阐明的途径中间体的光谱方法和合成标准的比较。A.进一步建立了生物转化截短侧耳素中间体的化学修饰类似物的平台，并用于产生具有增强的抗生素活性的半合成截短侧耳素衍生物。这些研究为今后在子囊菌异源宿主中表征其他担子菌天然产物的生物合成途径铺平了道路，并为不断增长的强效截短侧耳素抗生素类的进一步化学修饰开辟了新的可能性。截短侧耳素衍生物是从担子菌类真菌中获得的有效抗菌药物。在这里，作者报告了通过异源表达参与截短侧耳素生物合成的步骤的遗传表征，并产生具有增强的抗生素活性的半合成截短侧耳素衍生物。
The rise in antibiotic resistance is a major threat for human health. Basidiomycete fungi represent an untapped source of underexploited antimicrobials, with pleuromutilin—a diterpene produced by Clitopilus passeckerianus—being the only antibiotic from these fungi leading to commercial derivatives. Here we report genetic characterisation of the steps involved in pleuromutilin biosynthesis, through rational heterologous expression in Aspergillus oryzae coupled with isolation and detailed structural elucidation of the pathway intermediates by spectroscopic methods and comparison with synthetic standards. A. oryzae was further established as a platform for bio-conversion of chemically modified analogues of pleuromutilin intermediates, and was employed to generate a semi-synthetic pleuromutilin derivative with enhanced antibiotic activity. These studies pave the way for future characterisation of biosynthetic pathways of other basidiomycete natural products in ascomycete heterologous hosts, and open up new possibilities of further chemical modification for the growing class of potent pleuromutilin antibiotics. Pleuromutilin derivatives are potent antibacterial drugs obtained from Basidiomycete fungi. Here, the authors report the genetic characterisation of the steps involved in pleuromutilin biosynthesis through heterologous expression and generate a semi-synthetic pleuromutilin derivative with enhanced antibiotic activity.
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影响因子：
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作者：
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