Natural product discovery: past, present, and future

• Published in: Journal of Industrial Microbiology & Biotechnology Vol. 43; no. 2-3; pp. 155 - 176
• Main Authors: Katz, Leonard, Baltz, Richard H
• Format: Journal Article Book Review
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2016; Oxford University Press
• Subjects: Actinobacteria - genetics; Actinobacteria - metabolism; Actinomycetales; animal health; Animals; Anti-Bacterial Agents - isolation & purification; Anti-Bacterial Agents - metabolism; Antibiotics; Bacterial infections; Biochemistry; Bioengineering; Bioinformatics; Biological Products - chemistry; Biological Products - history; Biological Products - isolation & purification; Biomedical and Life Sciences; Biosynthesis; Biotechnology; Biotechnology industry; chemistry; Chemists; Computational Biology - history; Computational Biology - methods; Computational Biology - trends; crops; Drug Discovery - history; Drug Discovery - methods; Drug Discovery - trends; Drug Industry - history; Drug Industry - methods; Drug Industry - trends; drugs; FDA approval; Fermentation; Gene expression; Genetic Engineering; genome; genome mining; Genomes; History, 20th Century; History, 21st Century; Humans; Infections; Inorganic Chemistry; Laboratories; Life Sciences; Mass spectrometry; medicine; Metabolism; Metabolites; metabolomics; Microbiology; Microorganisms; Natural products; Pharmaceutical industry; Pharmaceuticals; Plant protection; proteomics; Review; screening; Secondary Metabolism; Secondary metabolites; sequence analysis; Studies; transcriptomics; United States > US; Fungi; Antibiotic; Secondary metabolite; Actinomycete; Discovery; Natural product; Genome mining; Streptomyces
• ISSN: 1367-5435; 1476-5535
• DOI: 10.1007/s10295-015-1723-5

Microorganisms have provided abundant sources of natural products which have been developed as commercial products for human medicine, animal health, and plant crop protection. In the early years of natural product discovery from microorganisms (The Golden Age), new antibiotics were found with relative ease from low-throughput fermentation and whole cell screening methods. Later, molecular genetic and medicinal chemistry approaches were applied to modify and improve the activities of important chemical scaffolds, and more sophisticated screening methods were directed at target disease states. In the 1990s, the pharmaceutical industry moved to high-throughput screening of synthetic chemical libraries against many potential therapeutic targets, including new targets identified from the human genome sequencing project, largely to the exclusion of natural products, and discovery rates dropped dramatically. Nonetheless, natural products continued to provide key scaffolds for drug development. In the current millennium, it was discovered from genome sequencing that microbes with large genomes have the capacity to produce about ten times as many secondary metabolites as was previously recognized. Indeed, the most gifted actinomycetes have the capacity to produce around 30–50 secondary metabolites. With the precipitous drop in cost for genome sequencing, it is now feasible to sequence thousands of actinomycete genomes to identify the “biosynthetic dark matter” as sources for the discovery of new and novel secondary metabolites. Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development.