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Natural products - Genome Mining and Biosynthesis

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Our group is interested in the discovery and biosynthesis of natural products. Compounds isolated from various terrestrial and marine sources such as bacteria, fungi and plants harbor enormous structural diversity and often exhibit strong, e.g. antibiotic or cytotoxic biological activities. Thus, it is not surprising that more than half of all approved drugs in human use are or are derived from natural products. For the development of new drugs, it is therefore still very important to discover natural products with novel activities and modes of actions and novel structural features.

Since traditional cultivation and isolation approaches frequently only lead to rediscovery of known compounds, we apply interdisciplinary, genome-based approaches to discover structurally novel and bioactive natural products from underexplored sources. Genome sequencing revealed large numbers of orphan or so-called “cryptic” biosynthetic pathways in many bacteria. With bioinformatic approaches it is possible to detect and, at least partially, predict promising biosynthetic pathways in sequenced bacteria, a procedure called “genome mining”. We use state-of-the-art synthetic biology tools to directly capture and express gene clusters of our interest in heterologous hosts, followed by structure elucidation and bioactivity evaluation. Natural product producers can be forced to produce the compounds of interest by environmental challenges or genetic manipulation of the gene cluster of interest. We routinely employ mass spectrometry-based approaches that aid in the rapid dereplication of natural products from complex mixtures and evaluation of different experimental conditions.

Natural products biosynthesis often embodies fascinating and highly effective biochemical reactions. We interrogate natural product pathways of our interest by analyzing important biosynthetic steps with heterologously expressed enzymes in vitro, complemented by in vivo experiments in the natural products producers. These insights will help us to engineer these biosynthetic pathways for the generation of novel compounds with improved structural or biological activities.