Microbial Drugs
The majority of the medically important antibiotic drugs are derived from secondary metabolites, which are produced by bacteria and filamentous fungi. Despite intensive world-wide efforts using alternative approaches, no other concept could so far surpass the historically successful strategy to exploit biologically active natural products as candidates for anti-infective drugs. The recently observed, increasing resistance of the human pathogens against antibiotics has prompted us to intensify our search for novel lead structures from microorganisms and fungi, which can be used as anti-infective drugs.
Leader
Our natural product chemistry workflow:
New strains are first cultivated on smaller scale (usually 500 mL) as shake cultures in Erlenmeyer flasks. After extraction with ethyl acetate, the resulting crude extracts are analyzed for their biological activities. In particular, we test for their antibiotic and antimycotic potential. At the same time, we identify already known metabolites in the extracts by coupling high-performance liquid chromatography (HPLC), UV/Vis spectroscopy with diode array detection (DAD) and mass spectroscopy (MS). This step, called dereplication, is important for quickly identifying already known compounds and focusing our work on new entities.
Only isolates that produce new and interesting metabolites are cultivated on a larger scale (2 – 5 L). After extraction of the fungal cultures, the bioactive compounds of interest are then purified by multiple chromatographic steps until the pure substance is obtained. We use classical column chromatography on silica gel, gel chromatography (Sephadex) and, above all, preparative reversed-phase HPLC for this purpose. To determine the chemical structure of the pure substances, we record nuclear magnetic resonance (NMR), high-resolution mass (HRMS) and UV/Vis spectra. Determining the structure of a small molecule is like solving a jigsaw puzzle: all spectral data must ultimately fit to a single structural proposal without any doubt.
If further biological testing reveals that a compound is particularly active and/or promising for drug development, it is produced on a gram scale after biological and chemical process optimization by fermentation in stirred fermenters with working volumes up to 350 L available. Examples include the antitumor agents epothilone and disorazole, the antibiotic sorangicin and the antifungal agent soraphen. We then make the compounds available to external cooperation partners for further development, e.g. for chemical derivatization to increase activity or to carry out preclinical studies.
Example: Terpenoids from the Wrinkled Peach Mushroom
The Wrinkled Peach Mushroom Rhodotus palmatus, also known as rosy veincap, is a pioneer mushroom on relatively fresh, rotting hardwoods, with a preference for elms. Although it has a circumboreal distribution, it is considered an endangered species in many countries due to its rarity. Nothing was known about the secondary metabolism of this fungus before our investigations, except that a general antimicrobial effect had been described for its culture extracts. The cultivation of this unusual basidiomycete led to the isolation, structure elucidation and biological evaluation of the first secondary metabolites of this fungus. Of these, the meroterpenoid rhodatin (1) had the most complex structure. In cooperation with Eike Steinmann (University of Bochum), we found that rhodatin (1) has an antiviral effect against hepatitis C virus (HCV). In addition, the twelve new sesquiterpenoids rhodocoranes A (2) – L (13) with cytotoxic and antimicrobial activities were obtained. They also have rare or previously completely unknown chemical scaffolds.
Link to the publication:
Story: New drugs from fungi
HZI researchers traveled to Yaoundé, Cameroon, for a workshop on the collection, culture and identification of fungal strains. A new research hub will strengthen natural product research in fungi in the country. [read more]
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