Strain Prioritization and Genome Mining for Enediyne Natural Products.
Strain Prioritization and Genome Mining for Enediyne Natural Products.
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DOI：
10.1128/mbio.02104-16
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发表时间：
2016-12-20
期刊：
影响因子：
6.4
通讯作者：
Shen B
中科院分区：
文献类型：
--
作者：
Yan X;Ge H;Huang T;Hindra;Yang D;Teng Q;Crnovčić I;Li X;Rudolf JD;Lohman JR;Gansemans Y;Zhu X;Huang Y;Zhao LX;Jiang Y;Van Nieuwerburgh F;Rader C;Duan Y;Shen B
烯二炔家族的天然产物对现代化学、生物学和医学产生了深远的影响，但迄今为止只有11种烯二炔被结构表征。在这里，我们报告了一项对3400种放线菌的基因组调查，发现81种菌株含有编码烯二炔聚酮合成酶磁带的基因，根据系统发育分析，这些菌株可以分为28个不同的分支。31个代表性菌株的基因组测序证实，每个分支都有一个独特的烯二炔生物合成基因簇。基因组邻域网络可以预测新的结构特征和生物合成的见解，可以用于发现烯二炔。我们确认了一个进化支作为新的C-1027生产者，其C-1027滴度明显高于原始生产者，并发现了一个新的烯二炔天然产物家族，天霉素（TNMs），对广泛的癌细胞系表现出强大的细胞毒性。我们的结果证明了从大量菌株收集中快速发现新的烯二炔的可行性。微生物基因组学的最新进展清楚地表明，土壤放线菌生产烯二炔的生物合成潜力尚未得到充分认识。一个巨大的挑战是开发创新的方法来发现新的烯二炔，并生产出足够数量的用于化学、生物和临床研究。这项工作证明了从大量菌株收集中快速发现新enediynes的可行性。新的C-1027生产商的C-1027滴度明显高于原来的生产商，将影响这种重要药物先导的实际供应。与fda批准的抗体-药物偶联物（adc）相比，tnm对各种癌细胞具有极强的细胞毒性，具有快速和完全的癌细胞杀伤特性，有望成为下一代抗癌adc的有效载荷候选物。对其他已发现的发现的后续研究有望发现新的烯二炔，从根本上扩大烯二炔家族的化学空间。
The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family.