The historical platform for antibiotics discovery provides a compelling example of the importance of natural products in medicine. The majority of the arsenal of antimicrobial agents that are still currently in use were discovered in the so-called “Golden Era of Antibiotics” in the 1950s and 1960s, when many pharmaceutical companies started industrialization of the isolation of bacterial strains from soil samples and screening culture extracts for biological activities. However, by the end of the 1980s it was becoming apparent that the same metabolites were being re-discovered over and over again in the screening programs. Due to the diminishing returns from this pipeline, many companies discontinued their natural products programs around the end of 1990s, and shifted their focus towards structure-based drug design and combinatorial chemistry. However, despite very strong investments into this field in the last 15 years, the efforts have not provided a single novel antimicrobial agent that has proceeded beyond preliminary clinical trials. One key problem has been that while many synthetic compounds with high efficacies towards their molecular targets have been successfully developed, it has become apparent that these compounds (unlike natural products) have difficulties in reaching their target site in vivo and in penetrating bacterial cell membranes. This has led to our current situation where even the World Health Organization has repeatedly stated that the world is running out of antibiotics.
At the same time when the interest of companies in natural products was dwindling, extensive research conducted by the Academic sector led to the identification of the gene clusters responsible for the biosynthesis of microbial natural products and yielded great insight into how these so-called secondary metabolites are made. In the past ten years, more detailed investigations using structural biology have elucidated at the molecular level the biosynthetic logic of all major classes of natural products (polyketides, non-ribosomal peptides, terpenes, ribosomally synthesized and post-translationally modified peptides).
Next generation sequencing provided the next breakthrough; genome sequencing projects revealed that Streptomyces have a tremendous genetic ability for production of secondary metabolites that far exceeded the expectations. The genomes typically harbor 30-40 gene clusters for production of these compounds, even though on average only 3-4 metabolites can be detected from cultures grown under laboratory conditions. Today it is fairly well recognized that Streptomyces are able to detect to the changing conditions in the soil and respond to various environmental signals by fine tuning the expression of their own metabolic pathways. The understanding of the biosynthesis of natural products has enabled the development of computer software for the bioinformatics analysis of these cryptic pathways and the recent advances in synthetic biology are beginning to provide tools for the artificial reconstruction or “refactoring” of these pathways for the discovery of novel bioactive natural products. These recent developments have reinvigorated the interest of many pharmaceutical companies in natural products and their proprietary microbial strain collections.
Updated 12 May 2018