Decoding and reprogramming complex biosynthetic pathways in microbes

Natural products from microorganisms are a highly prolific source for novel therapeutics, in particular for antiinfectives and antiproliferative agents. From a synthetic point of view, it is fascinating to learn that the most complex metabolites are assembled from simple biosynthetic building blocks by multienzyme processing lines. In recent years, advances in genome sequencing and developments of molecular tools have provided deeper insights into the genetic codes for these fine-tuned, multifaceted biocatalysts.

In this overview, I will demonstrate how genetic and chemical methods can be used in a synergistic manner to decode and engineer biosynthetic processing lines in microorganisms. Potential applications will be highlighted, such as reprogramming the biosynthetic code in the sense of combinatorial biosynthesis and synthetic biology. Furthermore, strategies to unlock the hidden * or cryptic - biosynthetic potential will be presented. In recent years it has become increasingly apparent that the vast number of predicted polyketide biosynthesis genes of microorganisms is not reflected by the metabolic profile observed under standard fermentation conditions. Since these gene clusters could code for the biosynthesis of drug candidates, it is desirable to test new strategies for their activation to make use of this largely untapped reservoir of natural products. Progress in engineering biosynthetic pathways and characterization of bioactive natural products from underexplored or neglected microorganisms will be presented.