Mining and unearthing hidden biosynthetic potential

Abstract

Genetically encoded small molecules (secondary metabolites) play eminent roles in ecological interactions, as pathogenicity factors and as drug leads. Yet, these chemical mediators often evade detection, and the discovery of novel entities is hampered by low production and high rediscovery rates. These limitations may be addressed by genome mining for biosynthetic gene clusters, thereby unveiling cryptic metabolic potential. The development of sophisticated data mining methods and genetic and analytical tools has enabled the discovery of an impressive array of previously overlooked natural products. This review shows the newest developments in the field, highlighting compound discovery from unconventional sources and microbiomes.

Fig. 1. Genome mining strategies.

Tools and strategies for mining genomic data and examples of natural products discovered through these methods. (syn-BNP synthetic-bioinformatic natural products, RiPPs ribosomally synthesized and posttranslationally modified peptides). The color code of the boxes around the compound names and icons indicates the strategy that was applied for the discovery of the respective compound: light orange—mining for core biosynthetic enzymes, light violet—mining for specific biosynthetic enzymes, light blue—bioinformatic structure prediction and chemical synthesis, brown—metabolomic approaches to link genes to metabolites and prioritize cryptic BGCs, yellow—resistance-genes-based genome mining, light red—genome mining for RiPPs, green—phylogeny-based genome mining.

Fig. 2. Accessing cryptic biosynthetic genes in native hosts.

Strategies for the activation of silent biosynthetic gene clusters in native hosts and examples of natural products discovered through these methods. (BGC biosynthetic gene cluster). The color code of the boxes around the compound names and icons indicates the strategy that was applied for the discovery of the respective compound: light blue—triggering natural product biosynthesis through chemical cues, light orange—activation of natural product biosynthesis through perturbation of epigenetic regulation, green—activation of natural product biosynthesis through ribosome engineering, light violet—activation of natural product biosynthesis through genetic engineering.

Fig. 3. Accessing cryptic biosynthetic genes in heterologous hosts.

Strategies for the activation of silent biosynthetic gene clusters in heterologous hosts and examples of natural products discovered through these methods. (BGC biosynthetic gene cluster). The color code of the boxes around the compound names and icons indicates the strategy that was applied for the discovery of the respective compound: Activation of natural product biosynthesis through heterologous expression of biosynthetic genes that are downregulated in the native producer (light orange) or from metagenomic DNA (green).

Fig. 4. Genome-guided discovery of natural products from unconventional sources.

Neglected bacteria, mushrooms, social amoebae, and higher organisms as sources and examples of natural products discovered from these organisms. The color code of the boxes around the compound names and icons indicates the source of the respective compound: light orange—microbes (neglected bacteria, mushrooms, and amoebae), green—higher organisms (plants, nematodes, fishes, birds).

Fig. 5. Genome-guided discovery of natural products from ecological interactions.

Symbiotic relationships among few or multiple partners as sources and examples of natural products discovered from these interactions. The color code of the boxes around the compound names and icons indicates the source of the respective compound: light orange—interactions among defined partners (endofungal bacteria, plant symbionts, and pathogenic bacteria), green—interactions among complex microbial communities (plant and human microbiota as well as marine sponges).