Activating cryptic biosynthetic gene clusters via ACTIMOT

Abstract

The mainstream strategy of genome mining relies on the homologous activation and heterologous expression of target biosynthetic gene clusters (BGCs). However, the efficiency of the current techniques available for new compound discovery hardly complements these efforts. In a recent publication in Science, Xie et al. reported their breakthrough progress in expediting the discovery of untapped chemical diversity from bacteria by establishing the leveraged know-how of ACTIMOT (Advanced Cas9-mediaTed In vivo MObilization and mulTiplication of BGCs), offering a new avenue to access the unexploited, and even unpredictable, biosynthetic potential of bacteria.

Keywords

Genome mining / Streptomyces / Natural products / ACTIMOT / CRISPR-Cas9

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Xiaoying Bian: Writing - review & editing, Writing - original draft.

Acknowledgment

The authors thank Dr. Jiaqi Liu for constructive discussions. This work was supported by the Shandong Provincial Natural Science Foundation (ZR2023ZD29), the Fundamental Research Funds of Shandong University (2023QNTD001), the Intramural Joint Program Fund of State Key Laboratory of Microbial Technology (SKLMTIJP-2024-04) and the SKLMT Frontiers and Challenges Project (SKLMTFCP-2023-05).

References

[1] D.J. Newman, G.M. Cragg, Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019, J. Nat. Prod. 83(2020) 770-803.

[2] M.H. Medema, T. de Rond, B.S. Moore, Mining genomes to illuminate the specialized chemistry of life, Nat. Rev. Genet. 22(2021) 553-571.

[3] L. Huo, et al.. Heterologous expression of bacterial natural product biosynthetic pathways, Nat. Prod. Rep. 36(2019) 1412-1436.

[4] J. Liu, X. Wang, G. Dai, Y. Zhang, X. Bian, Microbial chassis engineering drives heterologous production of complex secondary metabolites, Biotechnol. Adv. 59(2022) 107966.

[5] J. Wan, N. Ma, H. Yuan, Recent advances in the direct cloning of large natural product biosynthetic gene clusters, Eng. Microbiol. 3(2023) 100085.

[6] B.O. Bachmann, S.G. Van Lanen, R.H. Baltz, Microbial genome mining for accelerated natural products discovery: is a renaissance in the making? J. Ind. Microbiol. Biotechnol. 41(2014) 175-184.

[7] K. Scherlach, C. Hertweck, Mining and unearthing hidden biosynthetic potential, Nat. Commun. 12(2021) 3864.

[8] A.G. Atanasov, S.B. Zotchev, V.M. Dirsch, International Natural Product Sciences, T. & Supuran, C. T, Natural products in drug discovery: advances and opportunities, Nat. Rev. Drug Discov. 20(2021) 200-216.

[9] F. Xie, et al., Autologous DNA mobilization and multiplication expedite natural products discovery from bacteria, Science 386(2024) eabq7333.

[10] D.G.J. Larsson, C.F. Flach, Antibiotic resistance in the environment, Nat. Rev. Microbiol. 20(2022) 257-269.

[11] Y. Tong, T. Weber, S.Y. Lee, CRISPR/Cas-based genome engineering in natural product discovery, Nat. Prod. Rep. 36(2019) 1262-1280.

[12] M.N. Abbasi, et al., Recombineering for genetic engineering of natural product biosynthetic pathways, Trends Biotechnol. 38(2020) 715-728.

[13] A. Gavriilidou, et al., Compendium of specialized metabolite biosynthetic diversity encoded in bacterial genomes, Nat. Microbiol. 7(2022) 726-735.