Exploring and Exploiting Gene Networks That Regulate Natural Products Biosynthesis in Actinobacteria

Actinobacteria, particularly members of the order Actinomycetales, are one of the most prolific producers of natural products. Wild type strains usually produce very low amounts of natural products, while industry requires significantly higher yields to make production profitable. This justifies the development of extensive research programs aimed at strain improvement. Besides this, recent sequencing efforts revealed that actinobacterial genomes carry dozens of natural product biosynthetic gene clusters, which seem to be silent (or cryptic) under the conditions of traditional fermentation-guided screening procedures. Apparently, production of the natural compounds by actinobacteria is strictly regulated to maximise species competitiveness. Current crisis in the development of new classes of antibiotics against multidrug resistant bacterial pathogens has renewed interest in the different aspects of chemistry and biology of natural products. In this regard, better understanding of the regulatory circuits controlling natural product biosynthesis could greatly advance our abilities of novel antibiotics production. Using model systems, we will discuss what is known about the genetic architecture of regulatory networks that orchestrate natural products biosynthesis in actinobacteria. Then we describe how different elements of these networks could be used to improve strains, discover new molecules and develop new gene expression systems.