Research on antiinfective natural products

Antiinfective compounds from Atacama Desert actinomycetes

The Atacama Desert in Chile is the oldest and driest desert on earth. Our collaboration partner, M. Goodfellow from Newcastle University, UK, has isolated about 300 actinomycete strains from extreme hyper-arid and saline sampling sites. These strains, many of them from so-called rare actinomycete genera, are currently screened for production of novel metabolites. Furthermore, primary screening of these actinomycete strains for activity against the microorganisms B. subtilis, S. aureus, E. coli, P. fluorescens, and S. cerevisiae has indicated antiinfective activity of several strains that is currently followed up. Our aim is to isolate and characterize novel compounds active against pathogenic bacteria and fungi, potentially leading to the development of novel drugs against infectious diseases. This project is funded by the German Center for Infection Research (DZIF).

Antiinfective compounds from Indonesian actinomycetes

Indonesia is a so-called biodiversity hotspot with dense and species-rich flora and fauna in many parts of the country. In a collaborative project (ANoBIn, Accessing Novel Bacterial Producers from Biodiversity-rich Habitates in Indonesia) with other German as well as Indonesian partners, my group strives to identify novel anti-infective metabolites synthesized by Indonesian cyanobacteria. The project includes sampling excursions to isolate novel cyanobacteria strains, their identification and taxonomic characterization, a biological and chemical screening of all strains and the subsequent processing (cultivation, extraction, isolation and structure elucidation of active compounds) of the most interesting strains. This project is funded by the German Federal Ministry of Education and Research (BMBF).

Identification of compounds interfering with bacterial quorum sensing

Bacteria are not living isolated in their environment, but they communicate with each other, a capacity called quorum sensing. For example, bacteria can sense the amount of bacteria of their kind in a given environment, and only in case a critical cell number is reached, they might get pathogenic by e.g. forming biofilms or secreting toxins. Inhibition of this communication would therefor make bacteria think they are "alone", reducing the pathogenicity of these bacteria. We are currently screening several hundred actinomycete and cyanobacteria compounds and extracts for quorum sensing inhibition, and will subsequently isolate and characterize the natural products responsible for this effect. Also this project finally aims at finding novel compounds that can serve as a basis for antiinfective drug substances. This project is funded by the German Center for Infection Research (DZIF).

Antibacterial Cyclophanes from Nostoc

In collaboration with scientists at the University Greifswald, Germany (M. Preisitsch and S. Mundt), we are working on the structure elucidation of cyclophanes from the cyanobacterial genus Nostoc. A screening of cyanobacteria extracts revealed an extract from a Nostoc sp. as highly active against Gram-positive pathogens. The active compounds were isolated and structurally characterized, resulting in 5 new and 11 known cyclophanes. In addition to a pronounced antibacterial activity against S. aureus and S. pneumoniae, the compounds also displayed cytotoxicity. Presence of a carbamoyl group slightly enhances both antibacterial and cytotoxic activity. The results of this study have been published.

Currently, we are working on generating derivatives of the natural products for comparative activity testing. Furthermore, we have conducted a screening of > 100 cyanobacteria strains for novel analogs. This led to the isolation of novel compounds. Their structures and bioactivities will be described soon.

Screening of cyanobacterial extracts for various anti-infective activities

In collaboration with Cyano Biotech GmbH, Berlin, Germany, a library of 5700 cyanobacteria extract fractions (generated from extracts of > 300 individual strains) has been assayed against B. subtilis, M. luteus, E. coli, and P. fluorescens. Follow-up of interesting active hit fractions is currently under way.

Several cyanobacterial metabolites are potent protease inhibitors. As some proteases are interesting targets in anti-infective therapy, we will screen a library of about 700 cyanobacteria extracts against selected infection-relevant proteases from protozal pathogens (causing e.g. malaria or leishmaniosis) in collaboration with T. Schirmeister (Mainz, Germany).

Research on cytotoxic natural products

Development of Microcystins as anticancer drug leads

Microcystins, cyclic heptapeptides from cyanobacteria, can possibly be used as lead compounds for the development of drugs targeting certain types of cancers. First results of this project have been published. Together with the company Cyano Biotech GmbH (Berlin, Germany), we are currently working on the generation of optimized structures with higher selectivity for the tumor cells, reducing their general toxicity and thus the side effects of these compounds. This project is funded by the German Federal Ministry for Economic Affairs and Energy (BMWi).

Isolation and Characterization of the Cyanobacterial Toxin Causing Avian Vacuolar Myelinopathy (AVM)

AVM is a neurological disease of birds. It has been linked to certain cyanobacteria of the novel genus Aetoktonos by our collaboration partner, S. Wilde (University of Georgia, USA). We could isolate the cyanobacterium from AVM affected lakes and took it in culture. Using a cell-based assay, we could detect pronounced toxicity of extracts of the cyanobacterium. We are planning to isolate the novel cyanobacterial toxin causing AVM and thus clarify the etiology of AVM.

Research on natural product analysis

Natural Product Research and Mass Spectrometry

Mass spectrometry and Computer Assisted Structure Elucidation are powerful tools to aid in the structure elucidation of natural products. We have already contributed to the development of the software mMass to aid in the interpretation of tandem mass spectra of peptides (see the publication), and are currently working on optimizing the software to further simplify structure elucidation of these types of natural products.

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Funding