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For more than 50 yr, natural products have served us well in combating infectious bacteria and fungi. During the 20th century, microbial and plant secondary metabolites helped to double our life span, reduced pain and suffering, and revolutionized medicine. The increased development of resistance to older antibacterial, antifungal, and antitumor drugs has been challenged by () newly discovered antibiotics (e.g., candins, epothilones); () new semisynthetic versions of old antibiotics (e.g., ketolides, glycylcyclines); () older underutilized antibiotics (e.g., teicoplainin); and () new derivatives of previously undeveloped narrow-spectrum antibiotics (e.g., streptogramins). In addition, many antibiotics are used commercially, or are potentially useful in medicine for purposes other than their antimicrobial action. They are used as antitumor agents, enzyme inhibitors including powerful hypocholesterolemic agents, immunosuppressive agents, antimigraine agents, and so on. A number of these products were first discovered as antibiotics that failed in their development as such, or as mycotoxins.

Historically, nature has provided the source for the majority of the drugs in use today. This owes in large part to their structural complexity and clinical specificity. However, only a small percentage of known microbial secondary metabolites have been tested as natural-product drugs. Natural-product programs need to become more efficient, starting with the collection of environmental samples, selection of strains, metabolic expression, genetic exploitation, sample preparation and chemical dereplication. A renaissance of natural products-based drug discovery is coming because of the trend of combining the power of diversified but low-redundancy natural products with systems biology and novel assays. This review will focus on integrated approaches for diversifying microbial naturalproduct strains and extract libraries, while decreasing genetic and chemical redundancy. Increasing the quality and quantity of different chemical compounds tested in diverse biological systems should increase the chances of finding new leads for therapeutic agents.

Despite the fact that natural products have historically been a prolific source of new compounds, pharmaceutical drug discovery programs have moved away from natural products in favor of synthetic approaches. However, the abundance of synthetic compounds with similar functional groups and, therefore, limited chemical diversity has renewed interest in nature as a good resource for finding new ideas to be applied to the design of the next generation of drugs. One of the main issues for drug discovery programs based on microbial natural products is how to obtain the maximum potential from microbial strains in terms of chemical diversity of the metabolites produced. Several approaches are now available for enhancing the production and diversity of secondary metabolites from wild-type microorganisms. Automated comparisons of the metabolite profiles of microorganisms can be used as a valuable method for building libraries of natural products for drug discovery. Specific computer analyses of high-performance liquid chromatography chromatograms from organic extracts of fermented microorganisms can be used as a tool for increasing chemical diversity of collections, media improvement, evaluation of natural products libraries, and even determination of taxonomic correlations. Examples of what can be done using some of the new generation of software tools to compare profiles of secondary metabolites include the evaluation of extraction solvents and fermentation formats for the design of natural-product collections, and even the determination of relationships among strains from different origins.

Kosan Biosciences was founded on the principle that the chemical diversity of microbial metabolites, which for decades have been a rich source of natural-product drug leads and therapeutically important drugs, can be increased by altering the function of the genes and enzymes that govern the production of these metabolites. In particular, the predictable relationship between the structure and function of the modular type of microbial polyketide synthases has enabled genetic manipulation (“engineering”) of the producing organism for production of novel forms of various classes of naturally occurring compounds, such as macrolide antibiotics (erythromycins and ) and certain antitumor agents (epothilone D and the geldanamycins). This resembles the approach used by medicinal chemists who synthesize analogs and derivatives of lead compounds in an attempt to improve upon existing drugs or find new ones. Expression of the native or engineered polyketide synthase genes, as well as others that govern metabolite formation, in heterologous hosts is an important aspect of developing commercial systems for drug production. This chapter highlights advances made by Kosan Biosciences and some other groups in this area of natural-products drug research.

Microorganisms remain unrivalled in their ability to produce bioactive small molecules for drug development. However, the core technologies used to discover microbial natural products have not evolved significantly over the past several decades, resulting in a shortage of new drug leads. Advances in DNA-sequencing and bioinformatics technologies now make it possible to rapidly identify the clusters of genes that encode bioactive compounds and to make computer predictions of chemical structure based on gene sequence information. These structure predictions can be used to identify new chemical entities and provide important physicochemical “handles” that guide compound purification and structure confirmation. Industrialization of this process provides a model for improving the efficiency of natural-product discovery. The application of advanced genomics and bioinformatics technologies is now poised to revolutionize natural-product discovery and lead a renaissance of interest in microorganisms as a source of bioactive compounds for drug development.

The development of an economically viable production processes is a significant hurdle in the commercialization of natural products. A primary method of achieving this goal is through strain engineering. Evolutionary engineering has been practiced for decades in the form of classic strain improvement. The process of genetic diversification and functional screening has now become a powerful means of improving the function of diverse biological systems from genes and enzymes to whole genomes. Gene shuffling is a method for effecting genetic diversification in evolutionary engineering programs that incorporates recombination into the evolutionary algorithm. This approach dramatically accelerates the process of directed evolution and is arguably the most robust method for the purposeful manipulation of biological structure and function. This chapter reviews the theory and practice of gene shuffling-mediated evolutionary engineering in the context of commercial strain improvement. Described are examples of the improvement of commercial natural-product fermentation processes through the shuffling of individual genes, metabolic pathways, and whole genomes.

Since the early 1940s, the search for agents that may treat or ameliorate the scourge of cancer has involved all aspects of chemistry and pharmacology. Throughout these years, natural products have played an extremely important role as first the major source of drugs used for direct treatment, as scaffolds upon which chemists would practice their skill, and now as modulators of specific cellular pathways in the tumor cell. Even today, over 60% of the 140 plus agents currently available in Western medicine can trace their provenance to a natural-product source.

is a Pacific yew tree that produces Taxol. is one of the most well-studied plants in the world, and has provided a large number of alkaloids, including the clinically important antitumor agents vinblastine and vincristine. Both classes of antitumor agents interfere with tubulin-microtubule dynamics through opposite modes of action. They are the most renowned natural products, have been successfully brought to market, and have also served as leads for further optimization. This review highlights the chemical modification of diterpenoids and bisindole alkaloids, with an emphasis on structure-activity relationship studies and analog optimizations, leading to the discovery of a new generation of antitumor drugs.

Terpenoids, also referred to as terpenes, are the largest group of natural compounds. Many terpenes have biological activities and are used for the treatment of human diseases. The worldwide sales of terpene-based pharmaceuticals in 2002 were approximately US $12 billion. Among these pharmaceuticals, the anticancer drug Taxol® and the antimalarial drug Artimesinin are two of the most renowned terpene-based drugs. All terpenoids are synthesized from two five-carbon building blocks. Based on the number of the building blocks, terpenoids are commonly classified as monoterpenes (C), sesquiterpenes (C), diterpenes (C), and sesterterpenes (C). These terpenoids display a wide range of biological activities against cancer, malaria, inflammation, and a variety of infectious diseases (viral and bacterial). In last two decades, natural-product bioprospecting from the marine environment has resulted in hundreds of terpenoids with novel structures and interesting bioactivities, with more to be discovered in the future. The problem of supply is a serious obstacle to the development of most terpenoid compounds with interesting pharmaceutical properties. Although total chemical synthesis plays a less important role in the production of some terpenoid drugs, it has contributed significantly to the development of terpenoid compounds and terpene-based drugs by providing critical information on structure-activity relationships (SAR) and chiral centers as well as generating analog libraries. Semisynthesis, on the other hand, has played a major role in the development and production of terpenoid-derived drugs. Metabolic engineering as an integrated bioengineering approach has made considerable progress to produce some terpenoids in plants and fermentable hosts. Cell culture and aquaculture will provide a solution for the supply issue of some valuable terpenes from terrestrial and marine environments, respectively. Recent advances in environmental genomics and other “-omics” technologies will facilitate isolation and discovery of new terpenoids from natural environments. There is no doubt that more terpenoid-based clinical drugs will become available and will play a more significant role in human disease treatment in the near future.

Tremendous achievements have been made in Western medicine in the past that provide fast relief of symptoms at the disease sites, particularly under critical conditions. However, some are either ineffective or produce undesirable adverse effects, or are too costly in some complex diseases, especially chronic diseases. On the other hand, traditional medicines strive to focus on the balance of the body in a holistic manner. Traditional medicines are increasing popular in the Western world, as reflected in the name changes from “alternative medicines” to “complementary medicines” or even “integrative medicines.” Traditional Chinese medicines (TCM) have been used in China for more than 2000 yr and have always followed the philosophy and principle of restoration, i.e., the yin and yang (balance of the body). As an important part of the pharmaceutical sector, the Chinese herbal drug industry has made rapid progress over the past decades. This chapter provides a review of its current status, including challenges and opportunities, specifically with regard to modernization and globalization of TCM.