Targeted genome mining for microbial antitumor agents acting through DNA intercalation

Zhijie Zhao; Guiyun Zhao; Yi Chai; Wei Li; Kaihui Song; Wenbin Zhao; Hairong Li; Miaolian Wu; Zhan Zhou; Yi-Ling Du

doi:10.1016/j.synbio.2023.07.003

Targeted genome mining for microbial antitumor agents acting through DNA intercalation

Synth Syst Biotechnol. 2023 Jul 22;8(3):520-526. doi: 10.1016/j.synbio.2023.07.003. eCollection 2023 Sep.

Authors

Zhijie Zhao¹, Guiyun Zhao¹, Yi Chai², Wei Li¹, Kaihui Song¹, Wenbin Zhao³, Hairong Li³, Miaolian Wu⁴, Zhan Zhou^{3

4}, Yi-Ling Du^{1

4

5}

Affiliations

¹ The Fourth Affiliated Hospital and Department of Microbiology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
² Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³ Innovation Institute for Artificial Intelligence in Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
⁴ The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, 322000, China.
⁵ Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Hangzhou, 310058, China.

Abstract

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 uvrA-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 uvrA-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.

Keywords: Biosynthetic gene clusters; DNA intercalator; Genome mining; Microbial natural product; Tetracycline; UvrA-like protein.