Award details

A new drug discovery pipeline for animal African trypanosomiasis

Reference	BB/N007492/1
Principal Investigator / Supervisor	Professor Liam Morrison
Co-Investigators / Co-Supervisors
Institution	University of Edinburgh
Department	The Roslin Institute
Funding type	Research
Value (£)	299,816
Status	Completed
Type	Research Grant
Start date	01/07/2016
End date	31/12/2019
Duration	42 months

Abstract

In this project a consortium of researchers will join the Global Alliance for Livestock Veterinary Medicines (GALVmed) to advance novel paradigms in the intervention against Animal African trypanosomosis (AAT), a disease responsible for millions of livestock deaths in Africa each year. Chemotherapy remains the most important means of intervention against the causative Trypanosoma parasites but increasing resistance to the principal drugs used to treat the disease (diminazene and isometamidium) is jeopardising control efforts. Recently we have shown that a novel compound series of minor groove binders (MGBs) based on the clinically used anti-cancer drug distamycin, has profound activity against the veterinary trypanosomes T. vivax and T. congolense, both in vitro and in in vivo rodent models. One member of this series (MGB-BP3) is poised to enter clinical development against Clostridium difficile infection, having passed pre-clinical efficacy and safety trials with MGB-Biopharma. We will seek to design optimised anti-trypanosomal derivatives around the parent scaffold, with an ultimate aim of designing an optimised compound suitable for clinical development with GALVmed. To support the work, biological investigations into the trypanocidal actions of these molecules will proceed along with crucial work to assess the likelihood of resistance arising to this class, and the potential for cross-resistance to current treatments including the diamidine class of drugs (which also bind to the minor groove of DNA) and isometamidium. In parallel to the focus on this exciting new series of compounds, we will also use metabolomics to design much-needed new culture media to facilitate screening of other chemotypes, and systems biology approaches (comparative genomics, transcriptomics; pathway and metabolic modelling) to demarcate the full repertoire of metabolic targets - crucial to enable efficient drug discovery and target validation in veterinary trypanosomes.

Summary

A disproportionate burden of the world's infectious diseases (both human and veterinary) fall upon the African continent. Among the most devastating of the infectious agents of animals are the trypanosomes that cause Animal African Trypanosomosis (AAT). Transmitted primarily by tsetse and other biting flies, the disease is present in 40 African countries and affects nearly all domestic animals. The overall economic losses attributable to AAT are estimated at $4.75 billion per annum. These are losses borne principally by those who can least afford them: small-scale subsistence farmers and rural communities in AAT-affected areas of large parts of sub-Saharan Africa who rely on livestock for their livelihoods. Current AAT control tools rely extensively on trypanocidal drugs for the treatment of infected animals and for prophylaxis of infection. The drugs are widely available but were developed over 50 years ago and have significant limitations in terms of safety and increasingly lack efficacy against emergent drug-resistant trypanosomes. Over ten million km2 of Africa are infested by tsetse flies and thus affected by AAT; this represents a substantial portion of Africa's fertile and watered land. Within this area, millions of small-scale livestock keepers rely on an estimated 55 million cattle and 70 million sheep and goats for their livelihoods and food security. These regions are under sustained and increasing pressure to produce more food for growing populations, increasing per capita consumption of meat and dairy products, climate change and desertification all combine to require increased agricultural output within the potentially productive areas of sub-Saharan Africa. Losses arising from AAT are both direct (e.g. estimated annual death of 3 million cattle) and indirect as a result of productivity losses (e.g. benefits of up to $7,000 per km2 from removing AAT). The net effect is a significant constraint on growth and development of the dairy and beef sectors,as well as sheep and goat rearing in the regions affected. Trypanocidal drugs are the mainstay in the control of AAT because of the absence of realistic prospects for vaccines. Vector control has had limited success and showed poor sustainability, the more so in areas where non-tsetse fly transmission is important (e.g. parts of Africa, but particularly in the Far East and South America too). The Global Alliance for Livestock Veterinary Medicine (GALVmed) was founded to help channel global efforts into amelioration of the burden placed upon the world's food security brought about by various infectious diseases. With substantial funding from the UK Department for International Development and the Bill and Melinda Gates Foundation, GALVmed has become the primary agency involved in efforts to bring new drugs forward to treat AAT. In this proposal, experts at the Universities of Glasgow and Strathclyde, and the Roslin Institute of the University of Edinburgh, are coming together to develop a new class of compounds that has been shown to have profound efficacy against the causative agents of AAT, both in vitro and in rodent models of the disease. Chemical structures of those compounds optimised for trypanocidal activity in cattle will be developed with the intention of taking them into clinical development. We will additionally develop new culture systems for the relevant parasite species - a crucial step for rapid and routine screening of our candidate drugs but also large sets of unrelated compounds (chemical libraries), with minimal need for tests in animals. We will also use state of the art biological and computational methods to learn about the internal functioning of the causative parasites, in order to understand how this new class of compound works. This part of the project will also provide key information to allow other classes of compounds to be brought forward, giving an important input to a long-term pipeline of new drugs to treat AAT.

Impact Summary

It is estimated that some 45-50 million cattle, in addition to millions of goats, pigs and sheep, are at risk of African animal trypanosomiasis (AAT) in tsetse-infected areas of up to 10 million km2. Impacts include milk & beef production, calving rates and mortality, with an estimated annual cost to the region of $4.5 billion; a further key parameter is the impact upon draught animals such as equines and oxen, and their ability to work - clearly affecting agricultural production in many ways. The disease impact is particularly severe in endemic sub-Saharan regions, where the rearing of livestock is the main livelihood of small communities, and agriculture is the main driver of the developing economies. Currently, only two options exist for treatment of AAT: diminazene aceturate and isometamidium chloride. Both treatments are >50 years old and suffer from widespread resistance, but the resistance mechanisms are poorly understood, preventing effective surveys of resistance incidence. Both the identification of resistance markers and the development of new drugs are among the highest priorities for agricultural development in Africa. Our systems pharmacology platform will address both issues and is part of the BBSRC strategic priority of Animal Health, which is 'to support fundamental and strategic research leading to the development of intervention strategies for combating endemic and exotic infectious diseases (including vector borne and zoonotic disease)'. The identification of resistance mechanisms and markers will allow a far more accurate assessment of the AAT situation and inform intervention strategies. The introduction of new drugs will enable sustainable increases of agricultural production and food security - key BBSRC objectives. Furthermore, the proposed research addresses the causes of Antimicrobial Resistance (AMR), another major BBSRC priority area. Specifically, the work will contribute to 'the fundamental microbiology of organisms with known resistance prevalence in order to understand how resistance develops and is maintained, and develop mitigation strategies'. Importantly, the BBSRC strategy calls for 'Research that will inform strategies for combatting the development of AMR in managed animals', tying it into the food safety/agricultural themes. The direct impact of any improvement in AAT control on African food production would be very substantial at both local and regional levels. Importantly, we propose, in partnership with the major stakeholder GALVMed, a new and much-improved paradigm for addressing AMR and drug development, constituting a major new application of systems biology and conforming to the BBSRC call of 'Exploiting New Ways of Working'. Systems approaches to the Biosciences are in themselves a BBSRC priority and applications for the 'better countering of diseases or pests (including parasites) of crops or farmed animals' are especially encouraged. The generic platform of using metabolomics and transcriptomics in an integrated approach together with traditional biochemical and pharmacological techniques that we propose to create and validate here provides valuable training in key priority areas and as such impacts on the future UK skills base, with posts created for a senior postdoc in systems biology/pharmacology and a position in the bioinformatics analysis of the multi-disciplinary datasets, which will optimise structure-activity relationships within test series as well as create many novel insights in parasite metabolism. The skills, and indeed the entire systems-pharmacology approach, can be applied to many similar problems of AMR and lead optimisation in a drug development context. While the proposal is innovative the applicants have the combined track record and expertise to ensure genuine impact as here outlined, bringing together experts with major track records in polyomics, trypanosome genetics, drug resistance mechanisms and drug development for neglected parasitic diseases.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Industrial Partnership Award (IPA)

Associated awards:

BB/N007638/1 A new drug discovery pipeline for animal African trypanosomiasis

BB/N007999/1 A new drug discovery pipeline for animal African trypanosomiasis

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