A new drug discovery pipeline for animal African trypanosomiasis

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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 preclinical lead compounds in cattle and help optimise formulation-related issues.