The bleomycins (BLMs), a family of glycopeptide antibiotics, are currently used clinically in combination with a number of other agents for the treatment of malignant tumors. Other members of the BLM family include tallysomycins (TLMs), phleomycins and zorbamycin (ZBM). We previously cloned and characterized the biosynthetic gene clusters for BLMs, TLMs and ZBM. Applications of combinatorial biosynthesis strategies to the three biosynthetic machineries enabled the engineered production of several BLM analogs with unique structural characteristics and varying DNA cleavage activities, thereby providing an outstanding opportunity to study the structure-activity relationship (SAR) for the BLM family of anticancer drugs. We now report the engineered production of a new BLM-TLM-ZBM hybrid metabolite, named 6'-deoxy-TLM H-1, which consists of the 22-desmethyl-BLM aglycone, the TLM A C-terminal amine and the ZBM disaccharide, by heterologous expression of the zbmGL genes from the ZBM biosynthetic gene cluster in the Streptoalloteichus hindustanus ΔtlmH mutant strain SB8005. Evaluation of the DNA cleavage activities of 6'-deoxy-TLM H-1 as a measurement for its potential anticancer activity, in comparison with TLM H-1 and BLM A2, reveals new insight into the SAR of BLM family of anticancer drugs.The Journal of Antibiotics advance online publication, 23 August 2017; doi:10.1038/ja.2017.93.

中文翻译：

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6'-脱氧-他利霉素 H-1 的工程化生产和评估揭示了抗癌药物博莱霉素构效关系的新见解。


博来霉素（BLM）是一类糖肽抗生素，目前在临床上与许多其他药物联合用于治疗恶性肿瘤。 BLM 家族的其他成员包括他利霉素 (TLM)、腐草霉素和佐巴霉素 (ZBM)。我们之前克隆并表征了 BLM、TLM 和 ZBM 的生物合成基因簇。将组合生物合成策略应用于三种生物合成机器，能够工程化生产几种具有独特结构特征和不同 DNA 切割活性的 BLM 类似物，从而为研究 BLM 家族抗癌药物的构效关系 (SAR) 提供了绝佳的机会。我们现在报告了一种新的 BLM-TLM-ZBM 混合代谢物的工程生产，名为 6'-脱氧-TLM H-1，它由 22-去甲基-BLM 苷元、TLM A C 端胺和 ZBM 二糖组成，通过来自印度链球菌ΔtlmH突变菌株SB8005中ZBM生物合成基因簇的zbmGL基因的异源表达。与 TLM H-1 和 BLM A2 相比，评估 6'-脱氧-TLM H-1 的 DNA 切割活性作为其潜在抗癌活性的测量，揭示了对 BLM 家族抗癌药物的 SAR 的新见解。 《抗生素杂志》提前在线出版，2017 年 8 月 23 日； doi：10.1038/ja.2017.93。