Genome mining of Streptomyces sp. CB00271 as a natural high-producer of β-rubromycin and the resulting discovery of β-rubromycin acid,Biotechnology and Bioengineering

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Genome mining of Streptomyces sp. CB00271 as a natural high-producer of β-rubromycin and the resulting discovery of β-rubromycin acid
Biotechnology and Bioengineering ( IF 3.5 ) Pub Date : 2021-02-25 , DOI: 10.1002/bit.27732
Liwei Yi ₁ , Jieqian Kong ₁ , Yi Xiong ₁ , Sirui Yi ₁ , Ting Gan ₁ , Chengshuang Huang ₁ , Yanwen Duan _{1,

2,

3} , Xiangcheng Zhu _{1,

2,

3}

Affiliation

β-rubromycin (β-RUB) (1) is an efficient inhibitor of human telomerase possessing a unique spiroketal moiety as a potential pharmacophore and regarded as a promising anticancer drug lead. But the development of (β-RUB) (1) has long been hampered by its low titer and very poor water solubility. By adopting a genome mining strategy, an FAD-dependent monooxygenase RubN involving with the formation of the spiro system was applied as the probe and Streptomyces sp. CB00271 was screened out from our strain collection as an alternative natural high producer of β-RUB (1). After a series of fermentation optimizations, CB00271 could produce 124.8 ± 3.4 mg/L β-RUB (1), which was the highest titer up to now. Moreover, the enhanced production of β-RUB (1) in fermentation broth also led to the discovery of a new congener β-RUB acid (7), which was structurally elucidated as the acid form of β-RUB (1). Comparing to β-RUB (1), the substituted carboxyl group endowed β-RUB acid (7) much better solubility in serum and resulted in its higher activity towards tumor cells. Our work set up a solid base for the pilot-scale production of β-RUB (1) and its congeners to facilitate their future development as promising anticancer drug leads, and also provide an alternative and practical strategy for the exploitation of other important microbial natural products.

中文翻译：

链霉菌的基因组挖掘。CB00271作为β-红霉素的天然高产者和由此产生的β-红霉素酸的发现

β-rubromycin (β-RUB) ( 1 ) 是一种有效的人类端粒酶抑制剂，具有独特的螺旋缩酮部分作为潜在的药效团，被认为是一种很有前途的抗癌药物。但(β-RUB) ( 1 ) 的低滴度和极差的水溶性长期以来一直阻碍其发展。通过采用基因组挖掘策略，将涉及螺旋系统形成的FAD依赖性单加氧酶RubN用作探针和链霉菌。CB00271 从我们的菌株收集中被筛选出来，作为替代的天然高产 β-RUB ( 1 )。经过一系列发酵优化，CB00271 可产生 124.8 ± 3.4 mg/L β-RUB ( 1)，这是迄今为止的最高滴度。此外，发酵液中β-RUB( 1 )产量的增加也导致发现了一种新的同系物β-RUB酸( 7 )，其在结构上被阐明为β-RUB( 1 )的酸形式。与β-RUB( 1 )相比，取代的羧基赋予β-RUB酸( 7 )更好的血清溶解度，使其对肿瘤细胞具有更高的活性。我们的工作为 β-RUB ( 1 ) 及其同系物的中试生产奠定了坚实的基础，以促进其作为有前景的抗癌药物的未来发展，也为其他重要微生物天然的开发提供了一种替代和实用的策略。产品。

更新日期：2021-02-25

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