Max Crüsemann, PhD

Research

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 find and characterize natural products with innovative activities, modes of actions and structural features.

Since traditional cultivation and isolation approaches frequently only lead to rediscovery of known compounds, we apply interdisciplinary, “omics”-based approaches to discover novel and bioactive natural products from underexplored sources. Genome sequencing and the development of powerful bioinformatic approaches has revealed that many bacteria harbor a large number of uncharacterized biosynthetic pathways, organized in gene clusters. This procedure is called “genome mining”. We use state-of-the-art synthetic biology methods to directly capture and express prioritized gene clusters in heterologous hosts, followed by structure elucidation and bioactivity evaluation. In addition, 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 innovative mass spectrometry-based approaches that aid in the rapid dereplication of natural products from complex mixtures and the optimization of different experimental production conditions.

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

One of our main projects deals with the potent G protein inhibitor FR900359 (FR). In the last years, we have been studying the biosynthesis of this complex nonribosomal cyclic depsipeptide natural product in plant-associated bacteria. Two of our works were recently highlighted on journal covers: