Heike Brötz-Oesterhelt

Novel antibiotics and their mechanisms of action

University of Tübingen
Faculty in: IMPRS

Vita

PhD at the Institute of Medical Microbiology, University of Bonn, 1993-97
Industry positions at Bayer HealthCare and AiCuris GmbH & Co.KG (co-founder), Wuppertal
Professor for Pharmaceutical Biology, University of Düsseldorf, 2010-14
Full Professor and Department Head at IMIT since 2014
Co-speaker of the Cluster of Excellence “Controlling Microbes to Fight Infection”

Research Interest
The alarming worldwide spread of bacterial resistance causes an urgent need for new effective antibiotics. We study novel antibacterial agents, predominately bacterial products from various origins. Microbial natural products are privileged structures for antibiotic discovery, having emerged in a long period of co-evolution between antibiotic producing strains and bacterial target species.

One research focus is on the elucidation of the molecular mechanisms of action of these new agents by an array of microbiological, biochemical and genetic techniques. We apply our continuously expanding mode-of-action discovery platform, containing a variety of cell-based and extract-based assays to pinpoint the metabolic process inhibited. For the in-depth mechanistic characterization of a target, available technologies include mutant libraries, cutting-edge fluorescence and atomic force microscopy, interaction studies as well as an array of functional assays. Physiological consequences of compound application to bacterial cells are monitored to detect potential multiplicity of action. The overall lead potential of novel antibacterial agents is evaluated, uptake routes into bacterial cells are studied and together with collaborating chemists, compounds are modified towards increased therapeutic potential. In addition, we use our agents as tools to study the biological function of new targets and the cellular consequences of their inhibition.

Upper left depiction shows chemical structure of an acyldepsipeptide antibiotics congener. Upper right depiction shows acyldepsipeptide antibiotics bound to the proteolytic core of the compartmentalised protease ClpP. Bottom depiction shows bacillus subtilis labeled with a red membrane stain and FtsZ-GFP. — Figure 1. Mechanism of action of acyldepsipeptide antibiotics (ADEP). Structure of a representative ADEP congener (upper left). ADEP bound to its target, the proteolytic core of the compartmentalised protease ClpP (upper right). Bacillus subtilis labeled with a red membrane stain and FtsZ-GFP. Deregulation and activation of ClpP by ADEP leads to the degradation of the cell division pacemaker FtsZ. Bacterial cytokinesis stops and cells form long filaments.

Figure 1. Mechanism of action of acyldepsipeptide antibiotics (ADEP). Structure of a representative ADEP congener (upper left). ADEP bound to its target, the proteolytic core of the compartmentalised protease ClpP (upper right). Bacillus subtilis labeled with a red membrane stain and FtsZ-GFP. Deregulation and activation of ClpP by ADEP leads to the degradation of the cell division pacemaker FtsZ. Bacterial cytokinesis stops and cells form long filaments.

Available PhD Projects

Mode of action analysis of ticagrelor-derivatives (European Training Network position)
Mode of action analysis of new antibacterial natural products

Selected Reading

Illigmann A, Vielberg MT, Lakemeyer M, Wolf F, …, Brötz-Oesterhelt H. (2023). Structure of Staphylococcus aureus ClpP bound to the covalent active site inhibitor cystargolide A. Angew Chem Int Ed Engl. e202314028
Heilbronner S, Krismer B, Brötz-Oesterhelt H, Peschel A. The microbiome-shaping roles of bacteriocins. Nat Rev Microbiol. 2021 June 1. doi: 10.1038/s41579-021-00569-w
Zipperer A, Konnerth MC, Laux C, Berscheid A, Janek D, et al. (2016). Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535(7613):511-6.