Functional Metagenomics – On the hunt for novel products

imaginative 3D rendering of glass containers with DNA molecules

Natural products play a vital role in our everyday life- say in detergents, for the food and beverage production or in medicine. For the discovery of new natural products of bacteria a methodology called functional metagenomics opens up new possibilities.

Nature holds in store a mere incredibly large number of unexplored bioactive molecules- hidden treasures whose biotechnological potential is yet to be discovered. This is especially the case for bacterial metabolites. Despite novel cultivation methodologies, only 2-5 % of all bacteria are easily cultured in the laboratory. Thus, just a minor fraction of bacterial molecules is exploited in pharma and biotech industries, while most bacteria remain a treasure chest out of bounds. A promising means to get hold of the hidden treasures is functional metagenomics.

The underlying principle is to isolate DNA directly from the microbial community present in a highly complex sample. Then embedded in a carrier and cloned in a host, a metagenomic library is created; its clones each harbouring a snip of the environmental DNA. Just like with isolated environmental strains, the clones undergo a screening process specifically designed to identify those with a desired activity. That way functional metagenomics not only bypasses the restriction of sourcing only cultivatable microbes, but also facilitates easier gene identification. As it is located on the DNA insert, a gene´s potential position is narrowed down to that stretch of DNA.

The drawbacks of functional metagenomics are for one associated to the process of creating a metagenomic library. It can be a challenging task, especially if hosts other than E. coli are used in which case conventional procedures might not be sufficiently effective. When the library has been established, an adequate high- throughput screening assay needs to be in place to make the screening of the thousands of generated clones feasible. Only a small fraction of the clones will show the desired activity. This is partly due to prerequisite precursors, enzymes and specific cell machineries missing in the chosen host. This in turn can be circumvented by employing different host species but could result in a more challenging library production procedure.

The potential of functional metagenomics lies in the access to a yet untapped genetic diversity. Due to repeated isolation of known compounds among other things natural product search using cultivatable microbes lost its incentive especially for the pharmaceutical and biotech industry. Instead, industries turned to sourcing chemical libraries of synthetic and semi-synthetic compounds, despite the outranking structural diversity of natural compounds. As a consequence, natural product discovery came to a slack. Functional metagenomics boosts natural product discovery, and by doing so is the remedy to track down compounds of completely novel structure, such as metatricycloene.

In the mid- 1980s direct cloning of environmental DNA was first proposed and 10 years later for the first time a library constructed that way was successfully screened for cellulases. Since then many novel enzymes and bioactives were discovered by functional metagenomics. The focus, thereby, has been on soil, marine environments and microbiota associated to mammals. On plant associated microorganisms, however, screenings are rarely performed, in spite of their great potential for pharmaceutical, agro- and food industries as outlined in the recent review “Bioprospecting plant-associated microbiomes”.

The bottom line is that, despite its shortcomings, functional metagenomics provides access to an unexploited, diverse pool of unique microbial, natural products with great potential towards industrial application which would be inaccessible otherwise.

This blog bases on following paper: 
Müller CA, Obermeier MM, Berg G. Bioprospecting plant-associated microbiomes. J Biotechnol 2016, 235, p. 171-180.  
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