Discovery of Alternative Producers of the Enediyne Antitumor Antibiotic C-1027 with High Titers,Journal of Natural Products

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Discovery of Alternative Producers of the Enediyne Antitumor Antibiotic C-1027 with High Titers
Journal of Natural Products ( IF 3.3 ) Pub Date : 2018-01-18 00:00:00 , DOI: 10.1021/acs.jnatprod.7b01013
Xiaohui Yan ₁ , Hindra ₁ , Huiming Ge ₁ , Dong Yang _{1,

2} , Tingting Huang ₁ , Ivana Crnovcic ₁ , Chin-Yuan Chang ₁ , Shi-Ming Fang ₁ , Thibault Annaval ₁ , Xiangcheng Zhu _{3,

4} , Yong Huang ₃ , Li-Xing Zhao ₅ , Yi Jiang ₅ , Yanwen Duan _{3,

4} , Ben Shen _{1,

2,

6}

Affiliation

The potent cytotoxicity and unique mode of action make the enediyne antitumor antibiotic C-1027 an exquisite drug candidate for anticancer chemotherapy. However, clinical development of C-1027 has been hampered by its low titer from the original producer Streptomyces globisporus C-1027. Here we report three new C-1027 alternative producers, Streptomyces sp. CB00657, CB02329, and CB03608, from The Scripps Research Institute actinomycetes strain collection. Together with the previously disclosed Streptomyces sp. CB02366 strain, four C-1027 alternative producers with C-1027 titers of up to 11-fold higher than the original producer have been discovered. The five C-1027 producers, isolated from distant geographic locations, are distinct Streptomyces strains based on morphology and taxonomy. Pulsed-field gel electrophoresis and Southern analysis of the five C-1027 producers reveal that their C-1027 biosynthetic gene clusters (BGCs) are all located on giant plasmids of varying sizes. The high nucleotide sequence similarity among the five C-1027 BGCs implies that they most likely have evolved from a common ancestor.

中文翻译：

发现高滴度烯二炔抗肿瘤抗生素 C-1027 的替代生产商

强大的细胞毒性和独特的作用方式使烯二炔抗肿瘤抗生素 C-1027 成为抗癌化疗的绝佳候选药物。然而，C-1027 的临床开发因其原始生产者球孢链霉菌C-1027 的滴度较低而受到阻碍。在此，我们报告了三个新的 C-1027 替代生产者：链霉菌属 ( Streptomyces sp.)。CB00657、CB02329 和 CB03608，来自斯克里普斯研究所放线菌菌株保藏。与之前公开的链霉菌一起。CB02366 菌株是四个 C-1027 替代生产者，其 C-1027 滴度比原始生产者高出 11 倍。从遥远的地理位置分离出来的五个 C-1027 生产者根据形态和分类学是不同的链霉菌菌株。对五个 C-1027 生产商的脉冲场凝胶电泳和 Southern 分析表明，他们的 C-1027 生物合成基因簇 (BGC) 均位于不同大小的巨型质粒上。五个 C-1027 BGC 之间的高度核苷酸序列相似性表明它们很可能是从共同祖先进化而来的。

更新日期：2018-01-18

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