Fungal Rational Induction of Natural Products – FREE-NPs

The FREE-NPs project proposes to use bioinformatics approaches, in combination with metabolomics and genomics, to rationalize induction strategies for NP production. This project is based on the analysis of fungal Metabolic Biosynthetic Network to rationally select the appropriate culture conditions allowing increase in chemical diversity.
To achieve this goal, the key point lays in the use of accurate Metabolic Biosynthetic Network that will be able to precisely predict compound production according to the culture conditions. The efficient completion of the Metabolic Biosynthetic Network will be achieved using two different OMICS approaches. Genomic study of the strains will be used to reveal the hidden secondary metabolome present in both strain gene sequences. Metabolomic strategy, based on liquid chromatography coupled to high-resolution mass spectrometry, will be used to explore experimental compounds production during an OSMAC study (the One Strain Many Compound strategy consists in the growth of a microorganism in a large variety of culture media to provide a large chemical diversity). The latter result will provide: (1) after the deep dereplication of the chromatograms, a precise overview of the compounds produced by the two strains, and (2) information about metabolic regulation in the different culture media evaluated. All this information will clearly strengthen the Metabolic Biosynthetic Network. Finally, the analysis of those Networks will yield the selection of novel culture conditions able to expand observable natural products toward unprecedented chemical scaffold hidden in their genome.

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Nowadays, natural product research is still largely based on random screening of microbial extracts. This strategy is costly and time consuming and is one reason of the current decrease and mutation of natural product research in pharmaceutical companies. This is even amplified in the case of microbial drug discovery as the general strategies consist in the culture of a large number of microorganisms in various culture conditions to produce as much chemical diversity as possible. This project aims at developing rational approach to induce unprecedented microbial natural products with the fungus Penicillium chrysogenum as a model organism.
The FREE-NPs project proposes to use bioinformatics approaches, in combination with metabolomics and genomics, to rationalize induction strategies for NP production. This project is based on the analysis of P. chrysogenum Metabolic Biosynthetic Network to rationally select the appropriate culture conditions allowing increase in chemical diversity. To achieve this two different strains will be used, the highly studied Wisconsin 54-11255 and another one from the marine-sourced fungal collection of the “Mer, Molecules, Santé – EA2160” laboratory.
To achieve this goal, the key point lays in the use of accurate Metabolic Biosynthetic Network that will be able to precisely predict compound production according to the culture conditions. The efficient completion of the Metabolic Biosynthetic Network will be achieved using two different OMICS approaches. Genomic study of the strains will be used to reveal the hidden secondary metabolome present in both strain gene sequences. Metabolomic strategy, based on liquid chromatography coupled to high-resolution mass spectrometry, will be used to explore experimental compounds production by the two P. chrysogenum strains during an OSMAC study (the One Strain Many Compound strategy consists in the growth of a microorganism in a large variety of culture media to provide a large chemical diversity). The latter result will provide: (1) after the deep dereplication of the chromatograms, a precise overview of the compounds produced by the two strains, and (2) information about metabolic regulation in the different culture media evaluated. All this information will clearly strengthen the Metabolic Biosynthetic Network. Finally, the analysis of those Networks will yield the selection of novel culture conditions able to expand observable natural products for both P. chrysogenum strains toward unprecedented chemical scaffold hidden in their genome.
In conclusion, this project aims at rationalizing the OSMAC approach to provide improved culture conditions with the consequence of reducing the duration and thus the cost of such study. This, so called “Smart” OSMAC approach, will be one key step forward toward the renewal of natural product drug discovery programs in pharmaceutical companies, as well as in academic institutions.