SummaryFor 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 (1) newly discovered antibiotics (e.g., candins, epothilones); (2) new semisynthetic versions of old antibiotics (e.g., ketolides, glycylcyclines); (3) older underutilized antibiotics (e.g., teicoplainin); and (4) 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.It is unfortunate that the pharmaceutical industry has downgraded natural products just at the time that new assays are available and major improvements have been made in detection, characterization, and purification of small molecules. With the advent of combinatorial biosynthesis, thousands of new des4oeatives can now be made by a biological technique complementary to combinatorial chemistry. Furthermore, only a minor proportion of bacteria and fungi, i.e., 0.1-5%, have thus far been examined for secondary metabolite production. New methods are being developed to cultivate the so-called unculturable microbes from the soil and the sea. High-throughput screening (HTS) of combinatorial chemicals has not provided the numbers of high-quality leads that were anticipated. It has virtually eliminated the most unique source of chemical diversity, i.e., natural products, from the playing field, in favor of combinatorial chemistry. Combinatorial chemistry mainly yields minor modifications of present-day drugs and absolutely requires new scaffolds on which to build. Although comparative genomics is capable of disclosing new targets for drugs, the number of targets is so large that it requires tremendous investments of time and money to set up all the screens necessary to exploit this resource. This can be handled only by HTS methodology, which demands libraries of millions of chemical entities. Although such targets would be excellent for screening natural products, the industry has failed to exploit this unique opportunity and has opted to save funds by eliminating natural-product departments or decreasing their relevance in the hunt for new drugs. It is clear that the future success of the pharmaceutical industry depends on the combining of complementary technologies such as natural product discovery, HTS, integrative and systems biology, combinatorial biosynthesis, and combinatorial chemistry.
