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Design of the Natural Products Library (NPL)

Design of the Natural Products Library (NPL) at TSRI

Design of the Natural Products Library at TSRI took the following four major factors into consideration: (i) natural products of bacterial origin so that sufficient quantities of them can be readily produced by large-scale fermentation for follow up mechanistic and preclinical studies; (ii) genetic amenability of the producers so that recombinant strains overproducing the target natural products can be engineered to solve the supply bottleneck for ultimate production and commercialization; (iii) engineered production of natural product analogues by combinatorial biosynthesis strategies to complement traditional medicinal chemistry for lead optimization; and (iv) discovery of new natural products (new congeners of known scaffolds and new scaffolds) from untapped biodiversity to increase the odds of finding novel drug leads.

Key platform technologies supporting the Natural Products Library Initiative at TSRI include: (i) a collection of actinomycetes from diverse, un- and under-explored ecological niches; (ii) genomics-based technologies for surveying natural product biosynthetic potential and targeted discovery of novel microbial natural products; (iii) natural product titer improvement, structural diversity, and metabolic pathway engineering by combinatorial biosynthesis strategies; and (iv) overproduction of natural products as drug leads or drugs in engineered and industrial hosts.

Motivated by the optimism that each actinomycete strain encodes up 30 natural products on average, a collection of 10,000 strains in theory could encode the biosynthesis of 300,000 natural products.  Even if only 5% of the biosynthetic potential can be realized, this would translate into 15,000 natural products.  To put these numbers in perspective, the total number of natural products known to date from actinomycetes is estimated to be ~20,000, with the total number of natural products known to date from all microbial origins, i.e., actinomycetes, all other bacteria, and all fungi, estimated to be ~60-80,000.  Therefore, a library of 15,000 may represent the largest collection of natural products in the public domain, providing an unprecedented molecular diversity and an outstanding opportunity to screen novel biology for drug discovery. It is irrelevant if the natural products in the collection feature known or novel scaffolds, as long as they have not been exposed to biology of interest previously.