In their ongoing quest for new therapies against pathogens, scientists are focusing primarily on chemical and biological agents. These can function as antibiotics or stimulate the immune system. Discovering new drugs, characterising their functionality and optimising their properties are the three main goals of the department “Chemical Biology” at the HZI.
The core theme of the chemical biology department is the investigation of infection processes by applying 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 (1). 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 (2), 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 (3) are applied to recognize patterns in comparison to known compounds in order to obtain hints to 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 (3). We apply chemical-genetic interaction analysis using bacterial mutants, differential proteome analysis by DARTS (drug affinity responsive target stability), as well as peptide microarrays (4), metabolome analysis (5) and chemical probes.
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 tumor diseases 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 (6) and to antagonize the increasing antibiotic resistance and the resulting lack of antibiotically active compounds.
Therefore carriers, 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 typical small molecules. Our department’s objective is to provide innovative, in vivo effective advanced lead structures.
Prof Dr Mark Brönstrup
Head of the department chemical biology
+49 531 6181-3400
Bachelor & Master
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Bachelor, Master and PhD Theses
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Mit 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…