CMFI | New bioreporter approach increases chances of discovering unknown bioactive compounds | Heike Brötz-Oesterhelt

A big challenge in natural product research of today is rapid identification and exclusion of already known substances to free capacities for the exploration of new agents. Prompt information on bioactivities and mode of action (MOA) is required for rational compound optimization. It can also enable focusing on the isolation of compounds with unknown MOA, thus increasing the chances of discovering new chemical entities.

This idea led the team of Cluster of Excellence CMFI scientist Heike Brötz-Oesterhelt to develop a new bioreporter toolbox. The team of CMFI scientist Stephanie Grond performed state-of-the-art chemical analytics in the proof-of-concept study. The project was conducted in collaboration with the research group of Yvonne Mast at the Leibniz-Institute DSMZ–German Collection of Microorganisms and Cell Cultures and the study was mainly funded by the German Center of Infection Research (DZIF).

The bioreporter approach allows MOA-informed primary screening of bioactive compounds produced by a given strain without the need for initial compound enrichment or purification. The method is cost-effective, straightforward, and applicable along the entire purification pipeline. It works well with producer strains grown on agar, culture supernatants, extracts, fractions, and pure substances.

Combined with high-resolution methods in chemical analytics, the bioreporter technology adds a new dimension to the screening and purification process, which facilitates and speeds-up compound identification. A fraction of an agar plate with a producer strain often yields enough material to identify a known compound, which can then be deprioritized.

The bioreporter approach also detects when a producer strain synthesizes more than one antibiotic or if a single agent has more than one MOA. It immediately informs about the metabolic pathway inhibited, enabling the selection of focused follow-up assays to elucidate the molecular target.

Wex K W, Saur J S, Handel F, Ortlieb N, Mokeev V, Kulik A, Niedermeyer T H J, Mast Y, Grond S, Berscheid A, Brötz-Oesterhelt H.
Bioreporters for direct mode of action-informed screening of antibiotic producer strains.
CellChemBio (2021), doi: 10.1016/j.chembiol.2021.02.022.