Chemical Biology

The core theme of the chemical biology department is the investigation of infection processes by the use of chemical compounds. Complex cellular mechanisms are decoded by the individual analysis of cellular components, such as signaling proteins or enzymes that are inhibited or induced by chemical compounds. Subsequently their impact on the cellular phenotype can be described.

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.

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, differential proteome analysis by DARTS (drug affinity responsive target stability), as well as peptide microarrays (5), chemical probes and metabolome analysis (2). The latter belongs to the key areas of our department and serves also as a useful technique in the investigation of enzyme functions and biosynthetic pathways as well as in phenotyping of bacteria and biomarker detection in human and animal biospecimens.

Natural product synthesis and conjugation chemistry

Additionally, our department focusses 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)).

Quantifying the amount of antibiotics that is taken up by bacteria is complex and laborious which is why our department conducts intensive research on mass spectrometry-based methods to assess the penetration of drugs and drug candidates (1).

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.