Interfakultäres Institut für Mikrobiologie und Infektionsmedizin
Research team Prof. Dr. Brötz-Oesterhelt
Prof. Dr. rer. nat. Heike Brötz-Oesterhelt studied Biology in Bonn, Germany, and obtained her Diploma and PhD degrees in Microbiology. For more than 20 years, she has been working in antibacterial drug discovery in the academic as well as in the pharmaceutical industry setting. After her PhD, she joined the Anti-Infectives Department of Bayer HealthCare in Wuppertal, evaluating novel targets and developing lead structures. She headed project teams in structure optimization campaigns and coordinated all early research activities of the department. After 8 years in “big pharma”, she co-founded the Biotech company AiCuris. In 2010, she returned to academia as a professor for Pharmaceutical Biology at the University of Duesseldorf, and since 2014 she is full professor for Microbiology at the University of Tübingen heading the Department of Microbial Bioactive Compounds. Currently, she is managing director of the Interfaculty Institute of Microbiology and Infection Medicine, Tübingen, speaker of the Transregional Collaborative Research Centre TRR261 “Molecular Mechanism of Antibiotic Action and Production”, co-speaker of the Cluster of Excellence “Controlling Microbes to Fight Infection” (both funded by the German Research Organisation DFG) as well as deputy speaker of the partner site Tuebingen within the German Center of Infection Research (DZIF). Heike Brötz-Oesterhelt is particularly interested in molecular mechanisms of new antibiotic lead structures and operation modes of novel antibiotic targets.
Research focus
The Brötz-Oesterhelt team studies novel antibacterial agents still active against some of the most problematic bacterial pathogens (ESKAPE panel, mycobacteria etc.), including multi-resistant strains. Our primary focus is on the elucidation of the molecular mechanisms of action of these new agents by an array of microbiological, biochemical and genetic techniques. To this end we continuously expand our mode-of-action discovery platform, which already contains a variety of cell-based and extract-based assays for determining the disturbed metabolic pathway and narrowing-down on the process inhibited. Mutant libraries, resistance studies and assays with isolated enzymes are used for target identification. Physiological consequences of compound application to bacterial cells are carefully monitored to detect potential multiplicity of action. Such studies reveal the 'Achilles' heels' of multi-drug resistant bacteria.
Mode of action discovery platform of the Brötz-Oesterhelt group. General assays are available that rapidly yield hints on the metabolic pathway affected. Specific assay technology is developed for in-depth mechanistic characterization of each target. Atomic force and fluorescence microscopic studies are performed in collaboration with Filipp Oesterhelt and Peter Sass (see IMIT imaging platform).
Antibacterial agents are also used to study the function and operation mode of new antibacterial targets and their impact on bacterial physiology. Targeted interference with a biological process is instrumental in revealing its physiological function. Small molecule modulators (a general term used here to include activators as well as inhibitors) can be applied in a time-controlled manner and at a range of doses to trigger graduated effects. Perturbation can be monitored starting from the physiological norm and removal of the substance even allows for observation of regeneration processes.
With an applied interest, we also characterize the overall lead potential of novel compounds. Drug-target interactions are quantified in relation to minimal inhibitory concentrations for bacterial cells. The bacterial spectrum is investigated and efficacy is determined against multi-resistant clinical isolates. Counter-screens with eukaryotic cells are performed to assess prokaryotic specificity. The propensity for resistance development is determined as well as bacteriostatic versus bactericidal action, protein binding and chemical stability. Congener series are compared to obtain a first impression on the structure-activity relationship.
