Zhao Zhijie, Zhao Guiyun, Chai Yi, Li Wei, Song Kaihui, Zhao Wenbin, Li Hairong, Wu Miaolian, Zhou Zhan, Du Yi-Ling
The Fourth Affiliated Hospital and Department of Microbiology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Synth Syst Biotechnol. 2023 Jul 22;8(3):520-526. doi: 10.1016/j.synbio.2023.07.003. eCollection 2023 Sep.
Microbial natural products have been one of the most important sources for drug development. In the current postgenomic era, sequence-driven approaches for natural product discovery are becoming increasingly popular. Here, we develop an effective genome mining strategy for the targeted discovery of microbial metabolites with antitumor activities. Our method employs -like genes as genetic markers, which have been identified in the biosynthetic gene clusters (BGCs) of several chemotherapeutic drugs of microbial origin and confer self-resistance to the corresponding producers. Through systematic genomic analysis of gifted actinobacteria genera, identification of -like gene-containing BGCs, and targeted isolation of products from a BGC prioritized for metabolic analysis, we identified a new tetracycline-type DNA intercalator timmycins. Our results thus provide a new genome mining strategy for the efficient discovery of antitumor agents acting through DNA intercalation.
微生物天然产物一直是药物开发的最重要来源之一。在当前的后基因组时代，基于序列驱动的天然产物发现方法越来越受欢迎。在此，我们开发了一种有效的基因组挖掘策略，用于靶向发现具有抗肿瘤活性的微生物代谢产物。我们的方法采用类基因作为遗传标记，这些基因已在几种微生物来源的化疗药物的生物合成基因簇（BGC）中被鉴定出来，并赋予相应生产者自我抗性。通过对有天赋的放线菌属进行系统的基因组分析、鉴定含类基因的BGC，以及从优先进行代谢分析的BGC中靶向分离产物，我们鉴定出了一种新的四环素类DNA嵌入剂timmycins。因此，我们的结果为通过DNA嵌入作用高效发现抗肿瘤药物提供了一种新的基因组挖掘策略。
