Research Report 2010 2011 - Helmholtz-Zentrum für ...

108 SCIENTIFIC REPORTS | Infection and Immunity | Pharmaceutical Research
05 Pharmaceutical Research
TOPIC SPEAKER | Prof. Dr. Rolf Müller | Research Group Microbial Drugs | rom@helmholtz-hzi.de |
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS) | Department of Microbial Natural Products
Infectious diseases are one of the most important causes of death worldwide and contribute considerably to the need for clinical
treatment. Strong interdisciplinary collaboration in anti-infective research is necessary to translate hits from initial stages of
the drug development process to drugs in the clinic (“bench to bedside”) and to cope with the increasing antibiotic resistance of
pathogens. Isolation, identifi cation and optimisation of small molecules interfering with processes involved in infectious diseases
and modelling of the molecular interaction is crucial for understanding the infection process. The knowledge of the transport
mechanism and the drug-target interaction mechanism is required to optimise the impact of the drug while reducing unwanted
side effects. Most of the commercial drugs currently in use are derived from natural products or small molecules mimicking their
pharmacophore. The topic “Pharmaceutical Research” investigates these compounds with chemical biology approaches in order to
provide new classes of sustainable anti-infectives to the drug development pipeline.
The research topic was newly created after the establishment of the “Helmholtz-Institute for Pharmaceutical Research Saarland”
(HIPS) in late summer 2009. It was founded to harvest the potential of a fostered interaction between the HZI and the Department
of Pharmacy at Saarland University (UdS). The incorporation of HIPS adds pharmaceutical sciences to the Health research programme
of the Helmholtz Association. As translational research was identifi ed as one of the most important tasks for future health
research, the foundation of HIPS is a signifi cant contribution to close the translational gap in natural product based anti-infective
research.
The topic is composed of seven groups working at both sites, in Braunschweig (HZI) and Saarbrücken (HIPS). The three departments
at HIPS, namely “Microbial Natural Products” (MINS), “Drug Development and Optimization” (DDOP) and “Drug Delivery”
(DDEL) now commit their respective pharmaceutical expertise to the fi eld of infectious diseases. While MINS has traditionally
strong ties with the group “Microbial Diversity and Natural Product Discovery” (MWIS) at HZI, DDOP and DDEL have built up collaborations
with HZI groups, which already lead to the attraction of third party funding and exchange of scientists. The HIPS departments
are presented separately within this report.
The group “Chemical Biology of Infectious Diseases” (CBIO) as well as the groups “Medicinal Chemistry” (MCH) and “Identifi cation
of Molecular Targets of Anti-infectives”(BISA) were integrated into the topic “Pharmaceutical Research” because they engage in
highly overlapping activities: CBIO uses various chemical biology approaches to characterise the activity and the mode of action of
natural products. MCH uses medicinal chemistry and synthetic approaches to optimise these natural products as lead structures
and make them available in signifi cant quantities. BISA synergistically works on the identifi cation of antifungal compounds and on
deciphering their mode of action.
The group “Chemical Biology of Infectious Diseases” (CBIO) at HZI focuses on the elucidation of molecular mechanisms of infectious
processes by low-molecular drugs. They develop new, miniaturize and run existing activity assays to identify lead structures
and elucidate the mode of action of hits from compound libraries. These libraries consist of approx. 90,000 compounds with
unique collections of natural products from myxobacteria, compounds provided by cooperation partners, commercially available
libraries as well as substances synthesized in-house. CBIO has developed a semi-automated microscopic assay that provides hints
on the mode of action from the changes in the phenotype, coupled with statistical analysis of huge data sets. By software-based
photo analysis of the cells, a biological profi le of the compounds is generated. In a hierarchical cluster analysis, new substances
group with known compounds and similar profi les. The procedure could be validated and already gave valuable hints on new
modes of action and potential new drugs, which will be further investigated.