A new drug discovery pipeline for animal African trypanosomiasis

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.

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.

Some 45-50 million cattle, plus millions of goats, pigs and sheep, are at risk of African Animal Trypanosomosis (AAT) in tsetse-infected areas of ~10M km2. Impacts include milk & beef production, calving rates and mortality. Estimated annual cost to the region is $4.75 billion. AAT also impacts on draught animals such as equines and oxen, and their ability to work - clearly affecting agricultural production. The disease severely impacts sub-Saharan regions where livestock rearing is the main livelihood of small communities. Two primary options exist for treatment of AAT: diminazene and isometamidium. Both drugs are >50 years old and resistance to them is widespread. The development of new trypanocides and the identification of resistance markers and are among the highest priorities for sustainable agricultural development in Africa.

Our platform will address both issues and aligns with the BBSRC strategic priority of Animal Health 'to support fundamental and strategic research leading to the development of intervention strategies for combating endemic and exotic infectious diseases'. Our program will underpin progress towards new drugs against AAT through development of products and enabling technologies (screening methodology, understanding resistance mechanisms and mapping of biochemical pathways/drug targets). This, in partnership with GALVmed, will create a real clinical pipeline, with potential spin offs to treatments of related parasitic infections.
New drugs will enable sustainable increases of agricultural production and food security, key BBSRC objectives. The research also addresses the causes of Antimicrobial Resistance (AMR), another major BBSRC priority area: 'the fundamental microbiology of organisms with known resistance prevalence in order to understand how resistance develops and is maintained, and develop mitigation strategies'. The BBSRC strategy calls for 'research that will inform strategies for combating the development of AMR in managed animals', tying it to food security.

Beneficiaries of the project are principally subsistence farmers in sub-Saharan Africa, who are finding that current AAT treatments are no longer working, threatening their livelihoods and food security. GALVmed has been created to address these and similar problems, and we will also work directly with stakeholders such as the United Nations Food and Agriculture Organisation (FAO) Program Against African Trypanosomosis (PAAT). National and multi-national trypanosomiasis control programmes are major beneficiaries of this research: the development of new, affordable treatments against AAT is of primary importance to these groups, reversing the retreat in African livestock farming caused by drug resistance. Our proposal goes beyond the development of one class of new compounds, enabling the creation of greatly enhanced capacity for T. congolense and T. vivax drug screening through the much-needed development of culturing techniques and the creation of metabolic pathway maps. These will benefit the entire trypanosomiasis research community, and enable pharmaceutical companies to pursue drug development against AAT. The identification of resistance mechanisms to the current trypanocides and the establishment of standard sensitive and resistant strains is essential for AAT control. We will work with the Foundation for Innovative New Diagnostics (FIND) and local expert researchers (e.g. Prof. Matovu, Makerere University, Uganda), as well as collaborators from the University of Antwerp (Buscher, Delespaux) to capitalise on the findings and field-test proposed resistance markers.

The applicants have the track record, network and reputation necessary to rapidly move the research towards application - the field testing of drugs and resistance markers. The partnership with GALVmed will enable testing of advanced pre-clinical lead compounds in cattle and help optimise formulation-related issues.