Novel antibiotics and their mechanisms of action

Heike Brötz-Oesterhelt

Heike BroetzOesterhelt Jan19 red
  • 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

Research Interest

The alarming worldwide spread of bacterial resistance causes an urgent need for new effective antibiotics. We study novel antibacterial agents, predominately bacterial and fungal 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.

  • Figure IMPRS HBO
    click to enlarge

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

Mechanism of action of a new natural product antibiotic

Selected Reading

1) 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.

2) Schilling NA, Berscheid A, Schumacher J, Saur JS, Konnerth MC, et al. (2019) Synthetic lugdunin analogues reveal essential structural motifs for antimicrobial action and proton translocation capability. Angew Chem Int Ed Engl. doi: 10.1002/anie.201901589.

3) Thomy D, Culp E, Adamek M, Cheng EY, et al. Brötz-Oesterhelt H. (2019) The ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 reveals an accessory clpP gene as a novel antibiotic resistance factor. Appl. Environ. Microbiol. doi:10.1128/AEM.01292-19 (2019)