Chapter 5. Applying the genetics of secondary metabolism in model actinomycetes to the discovery of new antibiotics.

The actinomycetes, including in particular members of the filamentous genus Streptomyces, are the industrial source of a large number of bioactive small molecules employed as antibiotics and other drugs. They produce these molecules as part of their "secondary" or nonessential metabolism. The number and diversity of secondary metabolic pathways is enormous, with some estimates suggesting that this one genus can produce more than 100,000 distinct molecules. However, the discovery of new antimicrobials is hampered by the fact that many wild isolates fail to express all or sometimes any of their secondary metabolites under laboratory conditions. Furthermore, the use of previously successful screening strategies frequently results in the rediscovery of known molecules: the all-important novel structures have proven to be elusive. Mounting evidence suggests that streptomycetes possess many regulatory pathways that control the biosynthetic gene clusters for these secondary metabolic pathways and that cell metabolism plays a significant role in limiting or potentiating expression as well. In this article we explore the idea that manipulating metabolic conditions and regulatory pathways can "awaken" silent gene clusters and lead to the discovery of novel antimicrobial activities.