An integrated approach to tackling drug resistance in livestock trypanosomes.

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African Animal Trypanosomiasis (AAT), caused by tsetse-transmitted Trypanosoma congolense and T. vivax, is a major constraint on sub-Saharan African agriculture and food security. Control relies on the use of two main drugs, Isometamidium chloride (ISM - prophylactic) and Diminazene aceturate (DZ - therapeutic), both introduced over 50 years ago. ISM treatment failure is increasing across Africa, raising serious concerns about the sustainability of future AAT control. There is one therapeutic class currently in development, the benzoxaboroles (GALVmed/Boehringer Ingelheim; Galvmed are industrial partners on this proposal). Despite the reliance on these drugs in AAT, the understanding of drug failures, resistance mechanisms and epidemiology are poor, making it difficult to develop evidence-based mitigation strategies. This multidisciplinary project will use field, laboratory and modelling studies to test the overarching hypothesis that management of animal and human trypanosomiasis is threatened by an emerging failure of ISM to provide adequate treatment and prophylaxis. ISM resistance mechanisms and markers will be investigated through comparative biochemical, molecular and genomic analyses of resistant and susceptible Trypanosoma congolense, whilst relative fitness in hosts and vectors will be assessed. Field data will be collected to quantify trypanocide usage and effectiveness, assess resistance, isolate resistant T. congolense and measure epidemiological parameters. Resistance and spread will be investigated in silico with an AAT resistance model parameterised with field and experimental data on epidemiology and transmission of resistant and susceptible T. congolense. Finally, these findings will be extended to explore resistance in the benzoxaboroles. This is an opportunity for a step change in understanding AAT resistance, and will lead to development of strategies to maximise the useful lifetime of ISM, as well as new trypanocides such as the benzoxaboroles.

This project will fill important knowledge gaps that are currently limiting the development of sustainable control strategies for animal African trypanosomiasis (AAT). Elucidating the mechanisms of T. congolense resistance to isometamidium chloride (ISM), identifying a marker for diagnosis, and crucially better understanding the emergence and spread of resistance, as proposed in this study, are essential steps towards effective and sustainable control, including optimal use of novel drugs. We anticipate this project will enable and contribute to wider discussions on sustainable use of drugs in AAT control and help to drive this as a priority. Hence, the economic and societal impacts from this work include:

(1) Impact on disease control policies for sustainable use of trypanocides, leading to impacts on livestock farming in developing countries through reducing detrimental effects of resistance emergence.
Ultimate beneficiaries of the project are subsistence farmers in sub-Saharan Africa, who are finding that current AAT treatments are no longer working, threatening their livelihoods and food security. Approximately 50 million cattle, plus millions of other livestock, are at risk of AAT in tsetse-infected across an area of ~10M km2. AAT impacts include reduced milk yields, meat production, fertility, and draught power as well as mortality, and are estimated to cost billions (US$) to the region annually - estimated at $2.5 billion to Eastern Africa alone. The disease severely impacts sub-Saharan regions where livestock rearing is the main livelihood of small communities, including many countries on the DAC list of least developed countries. Tanzania has the third largest livestock population in Africa, and a high proportion of poor livestock keepers, with >4 million cattle threatened by trypanosomiasis.
Livestock keepers currently use 35-70 million doses of trypanocides annually. Two primary options exist for treatment of AAT: Isometamidium chloride and Diminazene aceturate . Both drugs are >50 years old and reported resistance to them is widespread. Outputs from this project will provide local (veterinary services), national (Ministry of Agriculture, Livestock and Fisheries), global (AU-PATTEC, FAO) and donor (GALVmed, DFID, BMGF) organisations with evidence to back up decision-making on sustainable use of drugs in AAT control. This project was co-constructed with local veterinary services and livestock keepers in Serengeti District, and national decision-makers in Tanzania, who have identified effective and sustainable trypanocide use as a particular concern. The same trypanocide drugs used for AAT are also used to reduce T. brucei circulation in cattle, which can be reservoirs for human African trypanosomiasis. Sustainable use of these drugs therefore has added benefits in prevention of human disease.

(2) Impact upon academic and industry AAT drug discovery and development programmes.
We know very little about how resistance emerges and spreads in livestock trypanosomes. This project will significantly advance this knowledge, both in terms of characterising mechanisms and rate of resistance emergence to ISM, and furthering our very scanty knowledge of the epidemiology of resistance in the field. The development of a mathematical model, that is developed and based on reliable data, will both inform on the dynamics of resistance and spread of ISM, and importantly be applicable to predicting resistance emergence and spread for novel trypanocides (such as the candidate compound currently under development by project partners GALVmed) - this output is a critical gap in knowledge and capability at present, which would be able to inform strategies to minimise resistance emergence and spread, and maximise the lifetime of both ISM and novel trypanocides. The applicants have links with relevant academic, industrial and policy stakeholders to enable dissemination and uptake of results in order to translate impact to farmers.