»AnthelNatProd«

More than one quarter of the global population is infected with parasitic worms. Praziquantel (PZQ) is the standard therapy for many flatworms, and the only effective drug used to treat schistosomiasis, a neglected tropical disease caused by blood flukes such as Schistosoma mansoni. Extensive use of PZQ over the past 40 years has already fostered reduced drug efficacy in some endemic areas. Moreover, despite two decades of regular mass drug administration programs, PZQ has failed to eliminate schistosomiasis. Yet, the pipeline for new antischistosomal drugs has dried up, largely because the complex life cycles of these parasites make high‑throughput screening expensive and labour-intensive. Consequently, we established a streamlined discovery platform to identify novel anthelmintics capable of replacing or complementing PZQ in treating schistosomes and related flatworms.

Microbial natural products are a longstanding and prolific reservoir of therapeutics in various fields. However, identifying antischistosomal compounds is hampered by the lack of high‑throughput screening methods for adult schistosomes. The free‑living nematode Caenorhabditis elegans with its rapid life cycle, simple and inexpensive culture, and genetic tractability has proven a powerful surrogate for preliminary anthelmintic screening. In this project we will screen a library of microbial extracts against C. elegans, prioritize the most active compounds and then confirm their efficacy against Schistosoma mansoni. Bioactivity-guided isolation of active molecules finally allows structure elucidation and potency assessment against several life-stages of the parasite such as larval, juvenile and adult worms. 

The basis of the screening process is the strain collection of the Fraunhofer IME consisting out of 120,000 different microorganisms. In addition to the discovery of new anthelmintic compounds this screening approach will provide useful information on the translation of bioactivity in C. elegans for schistosome screenings.

• Crude extracts of microbial cultures containing a multitude of natural products will be screened for activity against C. elegans.

• Highly active extract against C. elegans will be tested against S. mansoni.

• Extracts will be micro-fractionated. Screening for the activity of the individual fractions will reveal the compound(s) causing activity.

• Upscaling of strain cultivation purify active compound(s) on a mg-scale. Structure elucidation of unknown compound(s).

• Re-screening of isolated compounds for its potency and to exclude cytotoxicity.  

• Analysis of mode of action if unknown.