Natural products from underexplored pathways and extreme environments
Dr Florian Hubrich
Drugs with new chemical entities are urgently needed to tackle the emerging antibiotic resistance. We investigate natural products from underexplored pathways and extreme environments to characterize bioactive molecules with true structural novelty and their biosynthetic enzymes to bioengineer and improve potent anti-infectives.
Our research and approach
Natural products exhibit versatile bioactivities and provide valuable lead structures for drug discovery. Although the total number of characterized natural products increased over the last decades, only few of the compounds discovered had previously unknown chemical structures. However, structurally new chemicals are urgently required for the development of antibiotics with resistance-breaking properties and other active drugs. Recent advances in the field of natural product discovery indicate that there are several promising avenues to detect bioactive natural products with new chemical entities. The wealth of publicly available (meta)genomes conceals significant biosynthetic potential that has yet to be elucidated. In addition, there is an increasing number of talented microbial natural product producers that have been isolated but remain underexplored. Moreover, the isolation of natural products from habitats and organisms thought to lack the potential for natural product biosynthesis (e.g. hot sulfur springs) further supports the hypothesis that the known natural product chemical space covers only the tip of the iceberg.
The Hubrich Lab aims to contribute to the expansion of the currently known natural product chemical diversity and to characterize the biosynthetic enzymes involved. The resulting compounds and enzymes will be used to develop and improve anti-infectives through bioengineering. To achieve this goal, metabolic pathways of talented but neglected natural product producers such as cyanobacteria and microbes that colonize extreme habitats will be investigated. The research approach applies interdisciplinary methods of modern natural product research and chemical biology, including bioinformatics, molecular and synthetic biology, microbiology, enzymology and (bio)synthetic chemistry.
Team members
Dr Florian Hubrich
Group Leader
Research projects
Biosynthetic generation of non-natural antimicrobial lipopeptides
Peptide lipidation is valuable by improving the therapeutic and bioactive properties of peptides. All approved lipopeptide drugs are acylated which can cause cytotoxic effects. Genome mining suggests a treasure-trove of non-acylated lipopeptides to discover, for instance with isoprenoid moieties. Today, there are only a few characterized peptide prenyltransferases (PTs). Prenylated peptides are reported to possess the beneficial therapeutic properties of lipopeptides without sharing the toxicity. Unfortunately, no general understanding about the influence of prenylation at different amino acids or with various isoprenoid donors is currently available. We aim to fill in this gap by expanding the characterized PTs involved in lipopeptide natural product biosynthesis. To reach this goal, we establish a “plug-and-play” PTs library and examine the influence of distinct prenylated amino acids for the bioactivity of target peptides against multi-resistant bacteria. Based on this knowledge, we want to engineer efficient biocatalysts and apply them for lipopeptide (bio)synthesis to obtain new candidates for antimicrobial drug development.