Microbial‐derived natural products remain a major source of structurally diverse bioactive compounds and chemical scaffolds that have the potential as new therapeutics to target drug‐resistant pathogens and cancers. In particular, genome mining has revealed the vast number of cryptic or low‐yield biosynthetic gene clusters in the genus Streptomyces. However, low natural product yields—improvements to which have been hindered by the lack of high throughput methods—have slowed the discovery and development of many potential therapeutics. Here, we describe our efforts to improve yields of landomycins—angucycline family polyketides under investigation as cancer therapeutics—by a genetically modified Streptomyces cyanogenus 136. After simplifying the extraction process from S. cyanogenus cultures, we identified a wavelength at which the major landomycin products are absorbed in culture extracts, which we used to systematically explore culture medium compositions to improve total landomycin titers. Through correlational analysis, we simplified the culture optimization process by identifying an alternative wavelength at which culture supernatants absorb yet is representative of total landomycin titers. Using the subsequently improved sample throughput, we explored landomycin production during the culturing process to further increase landomycin yield and reduce culture time. Testing the antimicrobial activity of the isolated landomycins, we report broad inhibition of Gram‐positive bacteria, inhibition of fungi by landomycinone, and broad landomycin resistance by Gram‐negative bacteria that is likely mediated by the exclusion of landomycins by the bacterial membrane. Finally, the anticancer activity of the isolated landomycins against A549 lung carcinoma cells agrees with previous reports on other cell lines that glycan chain length correlates with activity. Given the prevalence of natural products produced by Streptomyces, as well as the light‐absorbing moieties common to bioactive natural products and their metabolic precursors, our method is relevant to improving the yields of other natural products of interest.

中文翻译：

---

用于优化兰霉素生产及其治疗潜力表征的快速分光光度检测

微生物衍生的天然产物仍然是结构多样的生物活性化合物和化学支架的主要来源，这些化合物和化学支架有潜力作为针对耐药病原体和癌症的新疗法。特别是，基因组挖掘揭示了该属中大量隐秘或低产的生物合成基因簇链霉菌属。然而，天然产物产量低——缺乏高通量方法阻碍了其改进——减缓了许多潜在疗法的发现和开发。在这里，我们描述了我们通过转基因方法提高兰霉素（安古环素家族聚酮化合物，正在研究作为癌症治疗药物）产量的努力氰链霉菌136. 简化提取过程后氰链霉菌培养物中，我们确定了主要兰霉素产品在培养物提取物中被吸收的波长，我们用它来系统地探索培养基成分以提高兰霉素总滴度。通过相关分析，我们通过确定培养上清液吸收但代表总兰霉素滴度的替代波长来简化培养优化过程。利用随后改进的样品通量，我们探索了培养过程中兰霉素的生产，以进一步提高兰霉素产量并缩短培养时间。测试分离的兰霉素的抗菌活性，我们报告了兰霉素对革兰氏阳性菌的广泛抑制，兰霉素对真菌的抑制，以及革兰氏阴性菌对兰霉素的广泛耐药性，这可能是由细菌膜排斥兰霉素介导的。最后，分离的兰霉素对 A549 肺癌细胞的抗癌活性与之前关于其他细胞系的报道一致，即聚糖链长度与活性相关。鉴于天然产物的普遍存在链霉菌属以及生物活性天然产物及其代谢前体常见的吸光部分，我们的方法与提高其他感兴趣的天然产物的产量相关。