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ABSTRACT
Frigocyclinone is a novel antibiotic with antibacterial and anticancer activities. It is produced by both Antarctica-derived Streptomyces griseus NTK 97 and marine sponge-associated Streptomyces sp. M7_15. Here, we first report the biosynthetic gene cluster of frigocyclinone in the S. griseus NTK 97. The frigocyclinone gene cluster spans a DNA region of 33-kb which consists of 30 open reading frames (ORFs), encoding minimal type II polyketide synthase, aromatase and cyclase, redox tailoring enzymes, sugar biosynthesis-related enzymes, C-glycosyltransferase, a resistance protein, and three regulatory proteins. Based on the bioinformatic analysis, a biosynthetic pathway for frigocyclinone was proposed. Second, to verify the cloned gene cluster, CRISPR-Cpf1 mediated gene disruption was conducted. Mutant with the disruption of beta-ketoacyl synthase encoding gene frig20 fully loses the ability of producing frigocyclinone, while inactivating the glycosyltransferase gene frig1 leads to the production of key intermediate of anti-MRSA anthraquinone tetrangomycin.
Graphical Abstract
Cloning and identification of the frigocylinone biosynthetic gene cluster provide a deep insight into the biosynthetic pathway and will contribute to development of novel antibiotics via genetic engineering.
Acknowledgments
We are grateful to Prof. Hans-Peter Fiedler for the kind gift of Streptomyces griseus strain NTK 97. Great thanks to Dr. Qiang Zhou (Shanghai Institute of Organic Chemistry) for the help of HPLC-MS and NMR analysis.
Author contribution
Mo J, Ye J, and Wu HZ designed the experiments; Mo J, Chen HZ and Hou BB carried out the experiments; Mo J, Ye J, Wu HZ and Zhang HZ analyzed the data; Mo J and Zhang HZ wrote the manuscript. All of the authors assisted with a critical reading of the manuscript.
Disclosure statement
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Supplementary material
Supplemental data for this article can be accessed here.
