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.

Synthetic Biology Advanced Natural Product Discovery

“…Identification of genes encoding secondary metabolic biosynthetic enzymes is a classic method for mining new NPs. Although structures of secondary metabolites are rich and diverse, their biosynthetic mechanisms are relatively conservative, for example, the similarity of amino acid sequences of core enzymes is high [16]. The scaffold core structure of many NPs is polyketide or peptide, which is controlled by the highly conserved polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS), respectively.…”

“…Another method to discover NPs is to analyze not only the coding genes but also the regulatory genes and resistance genes of the BGCs. With the growing understanding of NP biosynthetic pathways, it has been discovered that BGCs not only contain biochemical enzymes, but also regulatory elements, transporters and resistance genes [16]. Therefore, NP mining methods based on resistance or regulatory genes have been developed.…”

“…The required resistance gene often co-locates with the synthetic gene that encodes the production of antibiotics, so it can be used as a tag to discover putative antibiotics. Using this strategy, a new herbicide was identified by searching the dihydroxyacid dehydratase gene in the published fungal genomes [16].…”

“…The research strategy of genome mining is constantly developing and becoming diversified. In addition to the classic genome mining strategy based on enzyme function analysis, new research strategies such as mining based on system evolution, resistance gene, regulators, culture-independent single-cell and metagenomic have been reported [16]. Nowadays, the acquisition of big data has become easier and easier, but the research on the biological significance behind these data remains a challenge.…”

A bioprocess perspective on the production of secondary metabolites by Streptomyces in submerged co-cultures

“…These molecules are not directly involved in the cellular processes associated with growth and energy generation, but rather exhibit various ecological functions allowing the producer to thrive in its environmental niche. In the biotechnological context, the bioactivity exhibited by secondary metabolites is of great interest, as they may serve as promising drug leads (Scherlach and Hertweck 2021 ). The industrial developments in the field of secondary metabolites production were sparked by the discovery and large-scale manufacturing of penicillin, an antibiotic of fungal origin (Fleming 1929 ; Barreiro and García-Estrada 2019 ).…”