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.

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.