ACS Synth Biol. 2020 Jun 19;9(6):1460-1467. doi: 10.1021/acssynbio.0c00114. Epub 2020 May 19.
The complex life cycle of streptomycetes is closely related to their secondary metabolisms, all controlled by cascade regulations. Tiancimycins (TNMs) are ten-membered enediynes possessing great potential for antitumor drug development. However, their low yields in sp. CB03234 have greatly limited subsequent studies. Through transcriptome analysis and genetic characterization, we proved that WblA is one pivotal global regulator to repress the biosynthesis of TNMs. The deletion of could significantly enhance the production of TNMs, but also abolish the sporulation in CB03234. By constructing the NitR-ε-caprolactam inducible genetic switch, the expression of was governed in CB03234-NRW, thereby sustaining the overproduction of TNMs and recovering the normal sporulation upon induction, which were practical for the scaled-up production of TNMs. Considering the prevalence and conserved regulatory roles of WblA in streptomycetes, our developed strategy shall provide an effective and practical approach to facilitate titer improvement and discovery of natural products.
链霉菌复杂的生命周期与其次级代谢物密切相关，所有这些代谢物都受到级联调控的控制。天蚕霉素（TNMs）是一种具有巨大抗肿瘤药物开发潜力的十元烯二炔类化合物。然而，其在 sp. CB03234 中的低产量极大地限制了后续的研究。通过转录组分析和遗传特征分析，我们证明 WblA 是一个关键的全局调控因子，抑制 TNMs 的生物合成。缺失 可以显著提高 TNMs 的产量，但也会使 CB03234 中的孢子形成能力丧失。通过构建 NitR-ε-己内酰胺诱导型遗传开关，控制 CB03234-NRW 中 的表达，从而维持 TNMs 的过量生产，并在诱导时恢复正常的孢子形成，这对 TNMs 的规模化生产具有实际意义。考虑到 WblA 在链霉菌中的普遍性和保守的调控作用，我们开发的策略将为提高产量和发现天然产物提供一种有效且实用的方法。
