The core theme of the chemical biology department is the use of chemical compounds to investigate and modulate infection processes. Complex cellular mechanisms are decoded by the individual analysis of cellular components, such as signaling proteins or metabolites that are downregulated or induced by chemical compounds. We also aim to optimize these compounds to leads and clinical candidates by organic synthesis to treat bacterial or viral infections.
Discovering novel anti-infectives and elucidation of molecular mode of action
For many crucial components that play a role in the interplay – or the reciprocal fight – of host and pathogen neither inhibitors nor activators are known. Therefore, the first goal of the chemical biology department is to identify those by applying screening techniques (3). At the department’s disposal are diverse compound collections (ca 30,000 internal compounds, expandable through external collections) whereof the HZI natural product collection represents a unique feature. Our department provides substantial expertise for developing phenotypic test systems in medium throughput. Assays addressing bacterial biofilm formation(6), pathogen-induced pore formation, host pathogen interactions, p27 mediated signaling and growth of clinically relevant bacterial and viral pathogens (e.g. S. aureus, P. aeruginosa, V. cholerae, HCV, HIV, Dengue Virus) have been established by us. The infrastructure is part of the German Centre of Infection Research (DZIF) and, starting 2018, of the EU OPENSCREEN project.
To elucidate the molecular mode of action of bioactive compounds – especially those of natural products – is the second objective of the chemical biology department. Therefore a cascade of complementary techniques has been established. Profiling assays (4) are applied to recognize patterns in comparison to known compounds in order to obtain hints at the mode of action. The patterns are generated using impedance spectroscopy and high content imaging. Eventually, the target structure of an inhibitor is defined via more detailed mode of action studies (4). We apply chemical-genetic interaction analysis using bacterial mutants, peptide microarrays (5), chemical probes and metabolome analysis (2).
Bacterial metabolomics belongs to the key areas of our department and serves also as a useful technique for the phenotyping of bacteria and for biomarker detection in human and animal biospecimens.
Quantifying the amount of antibiotics that is taken up by bacteria is complex and laborious, which is why our department conducts intensive research on methods based on mass spectrometry, imaging and microbiology to assess the penetration of drugs and drug candidates (1). This research is carried out within the IMI Translocation and IMI ENABLE consortia.
Natural product synthesis and conjugation chemistry
Additionally, our department focuses on optimizing active compounds by functionalization. Recently, hybrid antibody-drug conjugates have been approved for the treatment of solid tumors and first data indicate a substantial therapeutic benefit. In our department we aspire to transfer this concept to infectious diseases by applying different targeting and effector formats in order to achieve an improved bacterial penetration (1) and to antagonize the increasing antibiotic resistance and the resulting lack of antibiotically active compounds. To this end, carriers, i.e. compounds that are exclusively internalized by bacteria, are conjugated via specific linkers to an active agent (conjugation chemistry (7)).
By developing novel synthesis routes for natural compounds with antibacterial and antiviral activity (8) we enable their use for conjugation chemistry. In addition, the compounds that are optimized with respect to activity and pharmacokinetic properties can be applied as classic small molecules. Our department’s objective is to provide innovative, in vivo effective advanced lead structures.
Bachelor & Master
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Bachelor, Master and PhD Theses
- Kleine Moleküle ganz groß – Mit Naturstoffen gegen Hepatitis CMit weltweit 130 Millionen Infizierten ist Hepatitis C eine der häufigsten Infektionskrankheiten. Die Therapien, die es derzeit gibt, sind langwierig, haben starke Nebenwirkungen und helfen nicht jedem Patienten. Florenz Sasse vom Braunschweiger Helmholtz-Zentrum für Infektionsforschung und Thomas Pietschmann vom TWINCORE in Hannover suchen gemeinsam nach neuen Wirkstoffen gegen das Hepatitis C-Virus. Hören Sie hier von ihren ersten Treffern und folgen Sie Florenz Sasse zu einer Bibliothek der anderen Art…