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Enzymatic generation of non-natural antimicrobial lipopeptides
Prenylation enhances the therapeutic and bioactive properties of peptides. Synthetic peptide prenylation requires protecting group chemistry and the use of toxic and environmentally harmful reagents. Prenyltransferases (PTs) offer a highly selective alternative that catalyze prenylation reactions under mild conditions. Although numerous peptide PTs have been characterized over the last decades, their diversity is far from fully explored.
Furthermore, there is a lack of systematic knowledge regarding the influence of prenylation at different amino acids or with different isoprenoid donors on the aforementioned properties of peptides. We aim to fill this gap by expanding the number of characterized PTs involved in the biosynthesis of lipopeptide natural products. To achieve this goal, we establish a “plug-and-play” PT library and investigating the influence of various prenylated amino acids on the bioactivity of target peptides against multidrug-resistant bacteria. Based on these findings, we aim to develop efficient biocatalysts and apply them to lipopeptide biosynthesis to identify promising candidates for the development of antimicrobial drugs.
Exploring the (bioactive) natural product biosynthesis of Thermovibrio ammonificans
Natural products are beneficial chemical molecules for their producers, e.g., for defense. Due to their very specific lifestyle and often small genomes, bacteria colonizing extreme habitats were longtime expected to be unable to produce natural products. However, there are a few natural products isolated from such environments but the biosynthesis remains enigmatic.
With funding of the Klaus Tschira Boost Fund, we now decipher the biosynthesis of ammonificins, bioactive natural products produced by the anaerobic hydrothermal vent bacterium T. ammonificans. Using a combination of methods from synthetic biology, microbiology and molecular biology we aim to understand how the extremophile produces the unique ammonificin chemical scaffolds. Moreover, we harness the biosynthetic enzymes and natural products to tackle emerging challenges such as antimicrobial resistance.