Recent advances in natural product discovery

Abstract

Natural products have been and continue to be the source and inspiration for a substantial fraction of human therapeutics. Although the pharmaceutical industry has largely turned its back on natural product discovery efforts, such efforts continue to flourish in academia with promising results. Natural products have traditionally been identified from a top-down perspective, but more recently genomics- and bioinformatics-guided bottom-up approaches have provided powerful alternative strategies. Here we review recent advances in natural product discovery from both angles, including diverse sampling and innovative culturing and screening approaches, as well as genomics-driven discovery and genetic manipulation techniques for both native and heterologous expression.

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

“…Mining of metagenomic libraries has also produced a number of new compounds (10-12), but it has not been generally adopted. If we hope to revitalize the use of natural products in the pharmaceutical industry, genome mining must be shown to be a high-throughput discovery process complementary or superior to existing methods (13,14). Here, we demonstrate the feasibility of this approach in a campaign to identify the full genetic repertoire of phosphonic acid natural products encoded by a collection of over 10,000 actinomycetes.…”

“…Second, the methodology needed for gene-based discovery of phosphonate biosynthetic loci has been rigorously established (17)(18)(19)(20)(21)(22)(23). This method relies on the fact that all but two characterized phosphonate biosynthetic pathways begin with the enzyme phosphoenolpyruvate (PEP) mutase (encoded by pepM) (14). Thus, amplification of an internal fragment of pepM with degenerate PCR primers is sufficient to identify strains or plasmid clones that encode phosphonate biosynthetic pathways.…”

Der Medizinnobelpreis 2015 - Auswirkungen auf die Phytopharmazie?

“…Dadurch wurde die Aufklärung und Herstellung des Moleküls Avermectin möglich, das in den Studien die höchste Wirksamkeit aufwies. Ein Beispiel für viele Wirkstoffe, die nicht nur aus rein chemisch-synthetischen Quellen stammen, sondern die durch die Evolution selbst hervorgebracht wurden und auf ihre Entdeckung durch Naturforschende warten - und davon, so wird geschätzt, gibt es noch sehr viele … [4]. …”

Copper and Manganese Cations Alter Secondary Metabolism in the FungusPenicillium brasilianum

“…Microbial natural products continue to represent an important source and inspiration for human therapeutics, 1 providing novel molecular scaffolds and biological activities. In the pos genomic era, information concerning the biosynthesis of secondary metabolite has been gained together with the observation that the number of genes encoding biosynthetic enzymes in fungi outnumbers the known secondary metabolites synthesized by these microorganisms, indicating that only a subset of biosynthetic pathway genes is expressed under standard laboratory culture conditions.…”