How to find effective natural compounds faster

The research group of Prof. Heike Brötz-Oesterhelt from the Interfaculty Institute of Microbiology and Infection Medicine at the Eberhard Karls University of Tübingen is looking for new antibacterial agents. A major challenge in today's natural product research is to discover and screen out already known substances at an early stage in order to have capacities for researching new active substances.

"We need information on bioactivity and mode of action as early as possible in order to focus on isolating compounds with unknown modes of action."– Heike Brötz-Oesterhelt

To this end, the researchers have developed a new bioreporter approach, which they have published in the journal Cell Chemical Biology. Bioreporters are microbial cells that have been genetically modified to produce a measurable signal in response to a specific agent in their environment - in this case, a color circle. This allows information on the mode of action of bioactive compounds to be generated as early as the primary screening stage, without the need to enrich or purify the substance. The method works along the entire purification pipeline, i.e. with culture supernatants, extracts, fractions and pure substances. Combined with high-resolution mass spectrometry, the biosensor panel is an efficient and sensitive tool for deciphering compounds. It immediately informs about the inhibited metabolic pathway, allowing the selection of targeted follow-up assays to elucidate the molecular target.

Balance 2021:

•     In corallopyronin A development, completion of transfer to industrial Clinical Research Organizations and upscaling of production to large scale (15,000 liters), and pivotal tox studies in dogs. (partially implemented)
•     Elaboration and publication of a roadmap of antibiotic development from translational academic research as part of DZIF participation in JPI-AMR.
•     Demonstration/confirmation of in vivo proof-of-concept for supportive therapy of Pseudomonas aeruginosa infections using PqsR-inverse agonistsin combination with an aminoglycoside antibiotic.

Current projects:

•     Demonstrate/confirm in vivo proof-of-concept for adjuvant therapy of Pseudomonas aeruginosa infections by using LecB inhibitors in combination with a standard-of-care antibiotic.
•     Nomination of a lead structure for use against Pseudomonas aeruginosa infections.
•     Identification and use of key transcriptional regulators to activate silent gene clusters and identify novel antibiotically active natural products.

(Text: DZIF Annual Report 2021; Translation: Leon Kokkoliadis)