Centre Algatech

Institute of Michrobiology, Academy of Sciences of the Czech Republic

Laboratory of algal biotechnology  

Bioactive compounds from cyanobacteria

Cyanobacterial produce amazing diversity of low-molecular metabolites mostly via the involvement by highly combinatorial biosynthesis pathways. These metabolites are believed to be tuned by evolution to interact with various biological targets and thus many of these structures are applicable in pharmacology and biotechnology. Aside from their pharmaceutical potential these molecules can act as relevant environmental toxins or can provide the cyanobacterium benefits in resource competition. Biosynthesic pathways of these compounds are encoded in biosynthetic gene clusters which facilitates the possible genome screening for novel secondary metabolites of genetic manipulation of these cluster for generation of novel chemical structures.

Our research group focuses on interaction on cyanobacterial metabolites with human cells from both pharmacological and toxicological point of view. In a broader context we are interested in the distribution of these metabolites in various habitats and their function in the ecosystem.

Screening for cyanobacterial secondary metabolites for their anticancer potential

There is a sustained need for development of new therapeutics due to poor prognosis of some cancer types and acquired resistance to drugs in clinical use. Microorganisms are an extremely valuable source of bioactive compounds with many having clinical applications. One of the key feature of the functional anticancer drug is the triggering the apoptosis (a way of regulated cell death) in the target cancer cells. Over past ten years we have performed a number of screening of cyanobacterial extracts and extract-derived fractions to find-out novel potential hit-compounds for further studies. We have obtained several novel chemical compounds (e.g. first natural oxadiazine nocuolin a) that induce apoptosis in cancer cells. In the most recent screening performed in collaboration with screening facility CZ-Openscreen we have evaluated bioactivity profiles of cyanobacterial fraction-derived library (1 600 individual fractions) in 18 human cancer cells together with 3 primary or near-primary cell lines in order to retrieve compound with selective anticancer activity. As the knowledge of the exact molecular target of the anticancer drugs is essential for its future applicability we are currently setting up in collaboration with our partners the methodological platform to uncover the mode of action and molecular targets of the newly discovered compound in our laboratory. This are employing the combination of molecular biology, genomics, metabolomics and analytical chemistry, most notably, thermal proteome profiling and genome wide CRISPR-Cas9 screening. The acquired knowledge will be essential for future preclinical testing.

Colaboration with:

  • Prof. Andreas Villunger (Univerity of Innsbruck, Austria)
  • Dr. André Mueller (Centre for molecular medicine in Vienna, Austria)
  • Dr. Dort Avni (MIGAL research Institute, Izrael)
  • Dr. David Sedlák (CZ-Openscreen)

Currently running project: Discovery of promissing chemotherapeutic candidates in cyanobacteria using high-throughput screening: mode of action and molecular targets.

If you are interested in this topic, please contact: RNDr. Pavel Hrouzek, Ph.D. (hrouzek@alga.cz, +420 384 340 470).

 

Potential therapeutics or environmental toxins

Thanks to the extensive research in the field of toxic cyanobacterial secondary metabolites over the last decades, several cyanobacterial toxin groups have been described in more detail, particularly hepatotoxic: microcystins and cylindrospermopsin, and neurotoxins including anatoxins and saxitoxins. However, given the enormous structural diversity of cyanobacterial metabolites and high concentrations of these chemical in cyanobacterial biomass it is likely that some of these structures may be relevant from ecotoxicological point of view.

Cyanobacterial lipopeptides

During our previous surveys of cytotoxic activity of cyanobacterial extracts, we have noted that some cyanobacterial strains are rich in production of cyclic lipopeptides exerting non-specific cytotoxic activity. We have consequently characterized the chemical structure of novel cyanobacterial lipopeptides puwainaphycins isolated from several soil and benthic cyanobacteria and demonstrated their amhiphilic structures cause rapid membrane damage and subsequent cell death in vitro. Aside from the cytotoxic effect puwainaphycins also exerts inhibition effect on several fungi including several important plant pathogens. Surprising is the chemical diversity produced by the individual cyanobacterial strains. The particular variants differ largely in the length of incorporated fatty acid and its functionalization. This structural diversity motivated us to study the structure activity relationships in puwainaphycin natural variants and chemically modified analogues.

In this topic we are interested in following research questions:

  • Can puwainaphycins act as environmental toxins or they can be utilized as potential antifungal drugs?
  • How do the structural features affect the cytotoxic and antifungal activity
  • What is the distribution of cyanobacterial lipopeptides in natural habitat? 

If you are interested in this topic, please contact: RNDr. Pavel Hrouzek, Ph.D. (hrouzek@alga.cz, +420 384 340 470).