Among clinical and industrial important microorganisms Streptomyces are the largest source of natural products. But only a fraction of all Biosynthetic Gene Clusters in their genome is active under laboratory conditions. During the last years research has clarified the role of cyclic dimeric 3`-5` guanosine monophosphate, c-di-GMP, as an ubiquitous secondary messenger. It is not only a regulator of morphological development but also of the production of natural products. This makes it an interesting starting point for the development of new natural products. The production and degradation of c-di-GMP builds up the first layer of regulation. A set of enzymes with redundant or at least overlapping function is responsible for these reactions. Subsequently several effectors such as BldD or σ^WhiG affect the expression of many target genes. Through countless interactions within this system - comprising feedback loops and bilateral regulation - a multilayered system makes it possible to have a finely regulated system that can react quickly to external and internal environments. In this system c-di-GMP helps to provide BldD its function as the so called “master regulator” in Streptomyces. Interfering in this system with genetic manipulations such as knockouts or overexpression of genes led to altering levels of c-di-GMP. Thus, it was possible to change the production levels of produced natural products and activate silent gene clusters.

c-di-GMP, Streptomyces, Natural products, Antibiotics, Second messengers