The heterologous expression of the Streptomyces natural product (NP) biosynthetic gene cluster (BGC) has become an attractive strategy for the activation, titer improvement, and refactoring of valuable and cryptic NP BGCs. Previously, a Streptomyces artificial chromosomal vector system, pSBAC, was applied successfully to the precise cloning of large-sized polyketide BGCs, including immunosuppressant tautomycetin and antibiotic pikromycin, which led to stable and comparable production in several heterologous hosts. To further validate the pSBAC system as a generally applicable heterologous expression system, the daptomycin BGC of S. roseosporus was cloned and expressed heterologously in a model Streptomyces cell factory. A 65-kb daptomycin BGC, which belongs to a non-ribosomal polypeptide synthetase (NRPS) family, was cloned precisely into the pSBAC which resulted in 28.9 mg/l of daptomycin and its derivatives in S. coelicolor M511(a daptomycin non-producing heterologous host). These results suggest that a pSBAC-driven heterologous expression strategy is an ideal approach for producing low and inconsistent Streptomyces NRPS-family NPs, such as daptomycin, which are produced low and inconsistent in native host.

中文翻译：

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通过链霉菌人工染色体载体系统达托霉素生物合成基因簇的异源表达。

链霉菌天然产物（NP）生物合成基因簇（BGC）的异源表达已经成为有价值，隐秘NP BGC的激活，效价提高和重构的诱人策略。以前，链霉菌人工染色体载体系统pSBAC已成功地用于大型聚酮化合物BGC的精确克隆，包括免疫抑制剂互变霉素和抗生素吡咯霉素，从而在多个异源宿主中产生了稳定可比的产量。为了进一步验证pSBAC系统是普遍适用的异源表达系统，克隆了玫瑰孢菌的达托霉素BGC并在链霉菌模型中异源表达细胞工厂。将一个属于非核糖体多肽合成酶（NRPS）家族的65 kb达托霉素BGC精确地克隆到pSBAC中，从而产生了28.9 mg / l达托霉素及其衍生物在大肠杆菌S. coelicolor M511（一种不生产达托霉素的产品）中异源主机）。这些结果表明，pSBAC驱动的异源表达策略是生产低和不一致的链霉菌NRPS家族NP（如达托霉素）的理想方法，而NP家族在本地宿主中生产的低和不一致。