FORESTRY BYPRODUCTS AS NOVEL THERAPEUTICS FOR PARASITE CONTROL IN LIVESTOCK

"Sustainable food production" - the process by which we feed the ever-growing world population - is at the top of every agenda. To deliver sustainable food production, it is essential that livestock live in excellent conditions and are healthy throughout their lives. Gastrointestinal parasitism is a direct challenge to this due to negative consequences on animal health and welfare and on the environment. In addition, parasitic disease directly results in a 30% increase in greenhouse gas emissions, which exacerbates climate change and so also threatens food production.
Drugs are often used to treat parasitic disease, but resistance to the drugs that kill these types of parasites is now widespread throughout the world, with a prevalence of nearly 100% in many countries. This leads to worldwide costs for food soaring by billions of pounds. In other words, the continuous use of drugs in livestock over the last 60 years has been positive in that it has increased livestock productivity and profitability, but the positive effects of the current generation of drugs (known as anthelmintics) is under threat due to global challenges, including antimicrobial resistance, climate change and maintenance of biodiversity. This project therefore directly addresses the impact that parasitism has on sustainable food production. It does this by using a low-value by-product for the UK's forestry industry and by incorporating this by-product into a next generation natural dietary supplement for livestock.
Natural compounds extracted from plants (often called plant secondary metabolites (PSM)), are known to disrupt the life cycle of parasitic nematodes both in the animal and in the environment. PSM can therefore act as anthelmintics, controlling the disease these parasites cause. However, using a single pure PSM is expensive. Attention has therefore turned to PSM-rich extracts that contain a complex mixture of PSM as this is cheaper. However, this approach is hampered by large variations in the PSM content. Variability in PSM-content across different extracts leads to irreproducible biological activity. Whilst studies have demonstrated the anthelminitic effects of individual PSMs and/or plant extracts, the use of PSM-rich extracts is still understudied. There are insufficient reports on the effect on biological activity of combinations of PSMs or the contributions of individual PSM. Repeatable production of extracts (and thus consistent biological activity) requires a more detailed understanding of both the chemistry contained within PSM-extracts and the biological interactions of the active compounds in PSM-extracts with the parasites.
Tree bark is particularly rich in antiparasitic PSM and it is very likely that the UK forestry industry creates enough bark waste to treat the UK livestock population, so long as the PSM-extract is administered at key times of parasite susceptibility. This project therefore brings together the forestry, livestock and bioprocessing industries with academic experts in parasitology, chemical biology, analytical and statistical analysis to understand the full extent of the interaction of the parasites with the tree bark extracts. In doing so, it will identify, and isolate compounds present in the bark extracts that demonstrate anthelmintic activity. This will enable the creation of an "Activity Index" - a tool to predict the anthelmintic activity of any future bark extract. This Activity Index will subsequently guide the characterisation of future large scale bark extracts, predicting their anthelmintic potential and optimise their inclusion in parasite control strategies. To achieve this, we will identify and test compounds for their presence in bark extracts and their anthelmintic activity. We will select potentially bioactive compounds on literature reports, preliminary evidence already available to us from previous work and novel work described in this proposal.

Plant secondary metabolites (PSM) include compounds with reported anthelmintic properties. To date, incorporation of PSM for parasite control has been hampered by variation in PSM content in tree-bark extracts, which results in variation in biological activity and thus inconsistency of effect. In this project, we will develop a workflow to address the limitation of irreproducible extract formation that has held back this approach to date. To achieve this, we will deliver a bark extract evaluation system that can usefully predict the biological activity of UK bark extracts for inclusion in parasite control strategies. Once complete, this will allow the creation of a realistic strategy to develop an integrated biorefinery based on the use of bark that can be applied on an industrial scale and so drive parasite control in livestock.
Compounds present in bark extracts that demonstrate anthelmintic activity will be identified and isolated. Four different strategies will be used to identify compounds: (i) compound identification through use of existing preliminary data; (ii) compound identification via a detailed literature review; (iii) compound identification from UK bark extracts via high resolution MS profiling targeted MS/MS analysis and association with biological activity and (iv) bioactivity guided compound isolation from "the most active UK bark extract". The implementation of this multi-dimensional research approach mitigates the risk of single-strategy-failure, as it is built on preliminary data and uses methods familiar to us to generate knowledge on active compounds in plant extracts. Central to this work is the ability to test the biological activity of all the identified compounds with two anthelmintic assays. Quantification of the biological activity of individual compounds and association of abundance of compounds with biological activity, will be used to create the bark Activity Index as a predictor of the anthelmintic activity of crude bark extracts.