Renewed interests in the discovery of bioactive actinomycete metabolites driven by emerging technologies

Abstract

Actinomycetes are prolific sources of bioactive molecules. Traditional workflows including bacterial isolation, fermentation, metabolite identification and structure elucidation have resulted in high rates of natural product rediscovery in recent years. Recent advancements in multi-omics techniques have uncovered cryptic gene clusters within the genomes of actinomycetes, potentially introducing vast resources for the investigation of bioactive molecules. While developments in culture techniques have allowed for the fermentation of difficult-to-culture actinomycetes, high-throughput metabolite screening has offered plenary tools to accelerate hits discovery. A variety of new bioactive molecules have been isolated from actinomycetes of unique environmental origins, such as endophytic and symbiotic actinomycetes. Synthetic biology and genome mining have also emerged as new frontiers for the discovery of bioactive molecules. This review covers the highlights of recent developments in actinomycete-derived natural product drug discovery.

Keywords: Streptomyces; actinomycetes; bioactive metabolites; co-culture; endophytes; multi-omics.

Figure 1.

Publication trend on actinomycetes from 1940 to 2018. The data were retrieved from the ISI Web of Science. The search term “actinomycetes” was used to extract the data from PubMed.

Figure 2.

Publication trend on rare actinomycetes from 1950 to 2019. The data were retrieved from PubMed. The search term “Rare actinomycetes” was used to extract the data from PubMed.

Figure 3.

Recently used approaches for the discovery of bioactive metabolites from actinomycetes. While exploration of actinomycetes from unique environments has been conducted for many years, iChip technique, diffusion chamber-facilitated culture, examination of endophytic and symbiotic bacteria, and metabolite profiling-derived discovery of bioactive metabolites represent recently developed approaches. Pictures of natural environments are taken from the creative commons and marked as “dedicated to public domains” (Weblinks: https://search.creativecommons.org/photos/32636618-a8a5-4dcf-81c6-de3ee87f5a6e; https://search.creativecommons.org/photos/c4b808de-03de-47a8-8c7a-3c8924ec0ff2; https://search.creativecommons.org/photos/3be5e8bc-3ac6-4e5c-a9f4-bb717e258998; https://search.creativecommons.org/photos/f22282da-d4f9-4400-8051-dfbdf8da0844)

Figure 4.

Representative examples of bioactive metabolites isolated from actinomycetes retrieved from the unique environmental origin (a), and symbiotic actinomycetes (b)

Figure 5.

Examples of new metabolites produced by endophytic actinomycetes (A), through co-cultures (B) and genome mining (C)

Figure 6.

Approaches for activation of silent secondary metabolites biosynthetic gene clusters. Co-culture techniques include culture of multiple organisms on agar plates, in droplets or membrane-partitioned systems. Genome-guided approach relies on identification of dormant gene clusters that follows their activation through genetic engineering or employment of activators.