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Abstract
Strain prioritization for drug discovery aims at excluding redundant strains of a collection in order to limit the repetitive identification of the same molecules. In this work, we wanted to estimate what can be unexploited in terms of the amount, diversity, and novelty of compounds if the search is focused on only one single representative strain of a species, taking Streptomyces lunaelactis as a model. For this purpose, we selected 18 S. lunaelactis strains taxonomically clustered with the archetype strain S. lunaelactis MM109T. Genome mining of all S. lunaelactis isolated from the same cave revealed that 54% of the 42 biosynthetic gene clusters (BGCs) are strain specific, and five BGCs are not present in the reference strain MM109T. In addition, even when a BGC is conserved in all strains such as the bag/fev cluster involved in bagremycin and ferroverdin production, the compounds produced highly differ between the strains and previously unreported compounds are not produced by the archetype MM109T. Moreover, metabolomic pattern analysis uncovered important profile heterogeneity, confirming that identical BGC predisposition between two strains does not automatically imply chemical uniformity. In conclusion, trying to avoid strain redundancy based on phylogeny and genome mining information alone can compromise the discovery of new natural products and might prevent the exploitation of the best naturally engineered producers of specific molecules.
Highlights
Natural products (NPs) display a remarkable array of chemical structures and bioactivities
In a more recent study, Tidjani AR and colleagues showed, by comparative genomics of Streptomyces strains belonging to the same species and isolated at the microscale, that almost-clonal strains can present important genetic content diversity providing them with unique metabolite production capabilities [13]
Taking our collection of 18 Streptomyces lunaelactis strains isolated from the same cave moonmilk deposits [14,15,16], we showed that, even when phylogeny analyses have demonstrated that multiple strains belong to one single species, the compounds produced can still highly differ in terms of quantity, diversity, and novelty
Summary
Natural products (NPs) display a remarkable array of chemical structures and bioactivities. It is difficult to estimate how many of these studies have really assessed the metabolite patterns at the “real” strain level This is due to the difficulty of precisely defining the notion of subspecies in Streptomyces and other important genera of “NP-makers”. Taking our collection of 18 Streptomyces lunaelactis strains isolated from the same cave moonmilk deposits [14,15,16], we showed that, even when phylogeny analyses have demonstrated that multiple strains belong to one single species, the compounds produced can still highly differ in terms of quantity (from basically nothing to economically viable production yields), diversity (structural forms only produced in one or few subspecies), and novelty (sometimes novel compounds are only produced by one single strain)
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