Concepts and Methods to Access Novel Antibiotics from Actinomycetes

Abstract

Actinomycetes have been proven to be an excellent source of secondary metabolites for more than half a century. Exhibiting various bioactivities, they provide valuable approved drugs in clinical use. Most microorganisms are still untapped in terms of their capacity to produce secondary metabolites, since only a small fraction can be cultured in the laboratory. Thus, improving cultivation techniques to extend the range of secondary metabolite producers accessible under laboratory conditions is an important first step in prospecting underexplored sources for the isolation of novel antibiotics. Currently uncultured actinobacteria can be made available by bioprospecting extreme or simply habitats other than soil. Furthermore, bioinformatic analysis of genomes reveals most producers to harbour many more biosynthetic gene clusters than compounds identified from any single strain, which translates into a silent biosynthetic potential of the microbial world for the production of yet unknown natural products. This review covers discovery strategies and innovative methods recently employed to access the untapped reservoir of natural products. The focus is the order of actinomycetes although most approaches are similarly applicable to other microbes. Advanced cultivation methods, genomics- and metagenomics-based approaches, as well as modern metabolomics-inspired methods are highlighted to emphasise the interplay of different disciplines to improve access to novel natural products.

Structure, Total Synthesis, and Biosynthesis of Chloromyxamides: Myxobacterial Tetrapeptides Featuring an Uncommon 6‐Chloromethyl‐5‐methoxypipecolic Acid Building Block

“…Mirroring their wide structural variety, NRPs fulfil diverse biological functions, including defense against competing microorganisms or chemotaxis . Several strategies are commonly employed for the discovery of new NRPs from bacteria, including genome mining, bioactivity‐guided isolation, and metabolome‐mining approaches . All three strategies have proven fruitful with myxobacteria, which are well‐established producers of SMs whilst being less extensively screened compared to, for example, the actinobacteria .…”

Dark, rare and inspirational microbial matter in the extremobiosphere: 16 000 m of bioprospecting campaigns

“…Our bioprospecting activities have focused on the phylum Actinobacteria (sensu Goodfellow [3]), the rationale for which we have rehearsed previously: unparalleled size and diversity of the taxon, extensive global and environmental distribution, continued discovery of new taxonomic radiations, genomes rich in natural product biosynthetic gene clusters (NP-BGC) and notable ecological and economic value. Although members of the genus Streptomyces continue to be the richest source of new actinobacterial specialized metabolites, members of non-streptomycete genera as pointed out by Hug et al [4] increasingly are being Bull and Goodfellow, Microbiology 2019 shown to produce chemically unique natural products, a fact well-illustrated by our work with Verrucosispora [5], Dermacoccus [6] and Lentzea [7].…”

“…Genomic-guided identification of new drug targets such as protein-protein interactions also will stimulate natural product bioprospecting given the extent of such interactions in nature. Moreover, as Hug et al [4] point out if production scale cultivation of target organisms compromises the exploitation of a promising natural product, culture-independent strategies that include metagenomics and heterologous expression of BGCs provide exciting approaches for the discovery of novel natural products among biosynthetic dark matter, as does the prospect of coupling genome sequencing with synthetic biology [33,34].…”

Metagenomic Insights Unveil the Dominance of Undescribed Actinobacteria in Pond Ecosystem of an Indian Shrine

“…Antibiotic discovery by conventional approach have the drawback of frequent rediscovery of known metabolites. Hence, focus has to be set on rare microorganisms to have a higher potential of novel metabolites [39, 40, 44]. As Actinobacteria are the well-known antibiotic producers and due to the difficulties of rare Actinobacteria isolation under normal laboratory conditions, metagenomic approach was set to systematically assess the Actinobacterial diversity with respect to the overall microbial structure from pond sediment.…”