An integrated approach to tackling drug resistance in livestock trypanosomes

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.