Abstract
Throughout history, natural products have significantly contributed to the discovery of novel chemistry, drug leads, and tool molecules to probe and address complex challenges in biology and medicine. Recent microbial genome sequencing efforts have uncovered many microbial biosynthetic gene clusters without an associated natural product. This means that the natural products isolated to date do not fully reflect the biosynthetic potential of microbial strains. This observation has rejuvenated the natural product community and inspired a return to microbial strain collections. Mining large microbial strain collections with the most current technologies in genome sequencing, bioinformatics, and high-throughput screening techniques presents new opportunities in natural product discovery. In this review, we report on the newly expanded microbial strain collection at The Scripps Research Institute, which represents one of the largest and most diverse strain collections in the world. Two complementary approaches, i.e. structure-centric and function-centric, are presented here to showcase how to leverage a large microbial strain collection for natural product discovery and to address challenges and harness opportunities for future efforts. Highlighted examples include the discovery of alternative producers of known natural products with superior growth characteristics and high titers, novel analogs of privileged scaffolds, novel natural products, and new activities of known and new natural products. We anticipate that this large microbial strain collection will facilitate the discovery of new natural products for many applications.
Highlights
Throughout history, natural products have significantly contributed to the discovery of novel chemistry, drug leads, and tool molecules to probe and address complex challenges in biology and medicine
We anticipate that this large microbial strain collection will facilitate the discovery of new natural products for many applications
Even if only 10% of the natural product diversity is captured within the crude extracts and partiallypurified fractions, there could be ϳ60,000 natural products waiting to be discovered by high-throughput screening (HTS) against emerging biology
Summary
During the 1990s, many pharmaceutical companies eliminated their natural product discovery programs in pursuit of high-throughput screening (HTS) and combinatorial libraries. The microbial strain collection at TSRI currently contains a total of 217,352 bacterial and fungal strains, of which 62,328 are actinobacteria, 14,465 other bacteria, 92,225 fungi, and 48,334 unidentified (bacteria or fungi) (Fig. 1A). These strains were isolated over the last eight decades with the majority acquired between 1940 and 2010 (Fig. 1C). The wide time range of collection allows for capture of chemical diversity based on evolution and environmental cues, which change over time and are impossible to reproduce in laboratory settings today These strains were isolated from 109 different countries (Fig. 1D) with factors such as climate and ecology that further increase the chemical and biological diversity. Structure-centric approaches rely on genomics and bioinformatics, whereas function-centric approaches rely on the innate biological activity of the natural products
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