Research focus
The focus of our research is the biosynthesis of natural products in actinomycetes. We are particularly interested in polyketide and aminoglycoside pathways and the development of molecular tools for their engineering in order to improve the product yields and generate new bioactive derivatives.
Research projects
- Polyketide engineering: Implementation of trans-acyltransferases (trans-ATs) as valuable tool for “bioderivatization” of natural products
- Aminoglycoside biosynthesos and producer strain optimization by pathway engineering
- Characterization of CRISPR-Cas systems in Actinobacteria
Polyketides (PK) are important secondary metabolites, widely used as antibiotics, antifungals, and drugs for other clinical applications. PK compounds are biosynthesized by complex multifunctional enzymes with modular architecture, the polyketide synthases (PKSs).
In our studies, we were particularly interested in the unusual and complex trans- and cis-PKS/NRPS assembly line of kirromycin and demonstrated that the pathway recruits two discrete ATs, KirCI and KirCII (Figure). We have shown that KirCI provides the biosynthetic machinery with malonate. The second AT, KirCII, was verified to transfer ethyl malonate onto the kirromycin ACP5 (Kirr-ACP5) and thus introduces the C-28 ethyl branch into the backbone of the antibiotic. More recently, in vitro studies revealed that this enzyme accepts other nonmalonyl-CoA substrates such as allylmalonyl-CoA, propargylmalonyl-CoA, and to a lesser extent azidoethyl- and phenylmalonyl-CoA. Alkyne-containing molecules, such as propargyl-derived compounds provide functional groups for further derivatization by “click chemistry”.
Thus, our current projects focuses on the implementation of the KirCII/ACP5 tool in heterologous assembly lines to achieve structural diversity and generate novel products with improved pharmacokinetic properties or new bioactivities.
Aminoglycosides (AGs) are an old class of antibiotic compounds, mostly applied in cases of infections that are caused by Gram-negative pathogenic bacteria. In contrast to the known and established antibiotic therapy, the potential use of AGs for treatment of human genetic diseases, human immunodeficiency and viral infections was first recently discovered and reported.
The promising AG-features became a great motivation to study this class of natural products in order to understand the intracellular production process. Our research group is mainly interested in the biosynthetic- and biosynthesis-related steps of selected AGs. The gained knowledge will be used to design strategies for strain engineering as well as for directed pathway modification and AG derivatization.
Present address: Symrise AG, R&D Microbiology, Muehlenfeldstrasse 1, 37603 Holzminden