Title: Fungal Metabolites as Novel Anthelmintics against Soil-Transmitted Helminthes Project Summary/Abstract It is estimated that over 2 billion people worldwide are suffering from complications due to infections with soil transmitted helminthes (STHs), but very little research is being conducted by human health pharmaceutical companies. In the USA, it is estimated that in distressed areas of poverty, just under 4 million people harbor undiagnosed STH infections. STH infections typically affect those living in poverty and underrepresented minority populations. Increased immigration, international travel and US soldiers returning from STH endemic countries are bringing undiagnosed helminth infections with them. There is an urgent need for new anti-parasitic agents for treating human gastrointestinal diseases caused by the STHs such as hookworm, ascarid, whipworm and strongyloides. Current treatment is by anthelmintics, which were derived from veterinary medicine rather than products developed specifically for humans. While in many instances these products are effective, the emergence of resistance coupled with low efficacy and mass indiscriminate drug treatment has resulted in the need for new therapeutics to be discovered and developed. The Mycosynthetix fungal library represents a source of novel metabolites with potential anthelmintic activity based on their activity against other targets of medical importance In Phase I we will evaluate extracts taken from 1500 fungi and 100 pure fungal metabolites for their ability to inhibit the motility of the infective stages of the human parasite Strongyloides stercoralis and the motility and development of the animal parasite Haemonchus contortus which will act as a surrogate for human GI parasites. Preliminary experiments against validated screens of these two organisms, demonstrated we were able to detect significant activity against one or both of these worms in Mycosynthetix fungal extracts. During Phase 1, it is anticipated that we will identify between 15-45 active fungal extracts/ compounds based on our past experience with infectious disease programs using whole organisms to evaluate crude microbial material, and on the preliminary data. Using appropriate biological methods we will prioritize these into 10-15 leads by activity and high therapeutic index as measured in comparison studies with mammalian cell lines. Active fungi will be cultured on a larger scale to obtain enough material for enrichment of the active component using column chromatography. At the end of Phase I, we will expect to be able to identify 5-10 Enriched Extract Leads having good activity and therapeutic index against one or both parasites. Phase II will be an expanded screening campaign and further evaluation of leads using both chemistry and pharmacology to satisfy the requirements of prospective pharmaceutical companies (human and/or animal) with interest in treating these diseases. Discovery and development of a new anthelmintic will satisfy a large and critical market need in both the human and animal health sectors. Emerging anthelmintic resistance against human and animal helminthiasis has led to resurgence in the identification and use of phytomedicines and other natural products to combat these infections. Mycosynthetix will identify, develop and market novel anthelmintics for treatment against STHs using pharmaceutical partners.
There is an overwhelming need for new anthelmintic medicines for human health. We will test unusual fungal metabolites for their ability to kill parasites and develop new medicines based on the active compounds we discover.