Niklas Janzing is an associated doctoral fellow in the graduate college "Natural products and natural product analogs against therapy-resistant tumors and microorganisms: new lead structures and modes of action" at HHU Düsseldorf.

Isolation and Characterization of Gyrase Inhibitors from Streptomycetes

The spread of antimicrobial resistance, especially in nosocomial infections, is a major threat for global health. Therefore, new antibiotics are urgently needed. Gyrase inhibitors are clinically relevant antibiotics, of which many are  synthetic derivatives of nalidixic acid. Originally, nalidixic acid was a fully synthetic compound. Yet, recently it was found to be produced naturally by Streptomyces species. Streptomycetes are a promising source for novel lead structures, as they are capable of producing a huge variety of bioactive substances that find application in medicine. Another gyrase inhibitor produced by Streptomycetes is novobiocin, which currently is not used clinically.
My PhD project is focused on the isolation of new derivatives of the natural gyrase inhibitors nalidixic acid and novobiocin from Streptomyces species. The objective is to identify novel derivatives for future research and development and, in case of novobiocin, find derivatives more suitable for clinical applications. The aim is to establish cultivation conditions for the bacterial strains that lead to the production of nalidixic acid and novobiocin, and their natural derivatives. To identify novel derivatives based on molecular networks, we will analyze culture supernatants and cell extracts using mass spectrometry-based metabolomics. Stepwise extraction and isolation of compounds from culture supernatants will be performed using liquid-liquid extraction as well as different chromatographic methods like flash- or column chromatography. The molecular structure of new derivatives will be elucidated by NMR, while the antibiotic potential of each compound will be evaluated through susceptibility testing against clinically relevant strains. Furthermore proteome-based approaches will be used for mechanism of action validation.