Discovery of novel secondary metabolites encoded in actinomycete genomes through coculture.

Ji Hun Kim,Namil Lee,Byung-Kwan Cho,Soonkyu Hwang,Yongjae Lee,Woori Kim,Bernhard O Palsson,Suhyung Cho

doi:10.1093/jimb/kuaa001

Abstract

Actinomycetes are a rich source of bioactive natural products important for novel drug leads. Recent genome mining approaches have revealed an enormous number of secondary metabolite biosynthetic gene clusters (smBGCs) in actinomycetes. However, under standard laboratory culture conditions, many smBGCs are silent or cryptic. To activate these dormant smBGCs, several approaches, including culture-based or genetic engineering-based strategies, have been developed. Above all, coculture is a promising approach to induce novel secondary metabolite production from actinomycetes by mimicking an ecological habitat where cryptic smBGCs may be activated. In this review, we introduce coculture studies that aim to expand the chemical diversity of actinomycetes, by categorizing the cases by the type of coculture partner. Furthermore, we discuss the current challenges that need to be overcome to support the elicitation of novel bioactive compounds from actinomycetes.

Highlights

Natural products are organic compounds produced by living organisms mainly in the form of secondary metabolites, most of which have therapeutic bioactivity, including antimicrobial, antifungal, and anticancer (Harvey, 2008)
Recent genome mining approaches have revealed an enormous number of secondary metabolite biosynthetic gene clusters in actinomycetes
We briefly introduce the conventional strategies to awaken the silent secondary metabolite biosynthetic gene clusters (smBGCs), and thereafter, focus on the coculture approach for unlocking the secondary metabolite production potential of actinomycetes

Summary

Introduction

Natural products are organic compounds produced by living organisms mainly in the form of secondary metabolites, most of which have therapeutic bioactivity, including antimicrobial, antifungal, and anticancer (Harvey, 2008). Coculture mimics ecological stresses like nutrient depletion during interspecies competition (Patin et al, 2018; van Bergeijk et al, 2020), and enables real-time monitoring of secondary metabolite bioactivities toward the participants of coculture via the analysis of morphological changes or cell density (Wu et al, 2010) Under these conditions, several ideal combinations of the producer and partner (inducer) have been identified, which efficiently induce production of novel secondary metabolites, including antibiotics, antifungals, anticancers, and siderophores. Introducing mutations in RNA polymerase or ribosomal proteins to change transcriptional or translational activity, respectively, led 66 strains out of 353 soilisolated actinomycetes to acquire an antibacterial-producing ability (Hosaka et al, 2009) Coculture is another effective culture-based strategy for discovering novel bioactive secondary metabolites from microorganisms by mimicking the environmental habitat where microbes continuously interact with nearby residents. BE-13793C (cytotoxicity) Arcyriaflavin E (cytotoxicity) Arcyriaflavin A Chojalactones A–C (cytotoxicity) Niizalactams A–C Prodiginine (antibiotics) 5-Alkyl-1,2,3,4-tetrahydroquinoline (antifungal)

12 Micromonosporaceae

Conclusion

Findings

Conflict of Interest