Bacterial Synthesis of Unusual Sulfonamide and Sulfone Antibiotics by Flavoenzyme-Mediated Sulfur Dioxide Capture
Bacterial Synthesis of Unusual Sulfonamide and Sulfone Antibiotics by Flavoenzyme-Mediated Sulfur Dioxide Capture
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DOI：
10.1002/anie.201506541
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发表时间：
2015-11-02
影响因子：
16.6
通讯作者：
Hertweck, Christian
中科院分区：
文献类型：
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作者：
Baunach, Martin;Ding, Ling;Hertweck, Christian
磺胺类药物，如磺胺和氨苯砜，是经典的抗生素，已在世界各地的临床使用。尽管结构相对简单，但实际上没有已知的天然产物具有这样的芳族磺酰胺或二芳基砜亚结构。我们报告了三个完全前所未有的，磺酰基桥接生物碱二聚体（磺胺二甲嘧啶A-C）的重组链霉菌物种窝藏整个夏霉素生物合成基因簇的意外发现。磺胺二甲霉素具有中等的抗分枝杆菌活性和有效的抗生素活性，甚至对多重耐药细菌。基因失活、互补和生物转化实验表明，一种黄素依赖酶（XiaH）在磺胺二甲霉素生物合成中起关键作用。XiaH介导了一个基于自由基的三组分反应，涉及两个当量的Xiaamycin和二氧化硫，这让人想起自由基苯乙烯/SO2共聚。
Sulfa drugs, such as sulfonilamide and dapsone, are classical antibiotics that have been in clinical use worldwide. Despite the relatively simple architectures, practically no natural products are known to feature such aromatic sulfonamide or diarylsulfone substructures. We report the unexpected discovery of three fully unprecedented, sulfonyl-bridged alkaloid dimers (sulfadixiamycins A-C) from recombinant Streptomyces species harboring the entire xiamycin biosynthesis gene cluster. Sulfadixiamycins exhibit moderate antimycobacterial activities and potent antibiotic activities even against multidrug-resistant bacteria. Gene inactivation, complementation, and biotransformation experiments revealed that a flavin-dependent enzyme (XiaH) plays a key role in sulfadixiamycin biosynthesis. XiaH mediates a radical-based, three-component reaction involving two equivalents of xiamycin and sulfur dioxide, which is reminiscent of radical styrene/SO2 copolymerization.