Drug resistance is an increasing problem for many diseases worldwide. Trypanosomes are tsetse-fly transmitted single-celled organisms that cause serious disease in cattle – African Animal Trypanosomiasis (AAT), mainly in sub-Saharan Africa, where approximately 60 million cattle are at risk and AAT kills 3 million each year. The main measure farmers have to combat AAT is drug treatment, however we only have two main drugs, both of which are >50 years old and widely used. Resistance to these drugs is increasingly reported, and there are very few drugs in the development pipeline, meaning the current control methods have very doubtful sustainability. Despite being such a significant issue, we know very little about how trypanosomes resist the effect of the drugs, and how AAT drug resistance emerges and spreads. These knowledge gaps limit our ability to mitigate the problem.

In northern Tanzania, farmers have been reporting drug treatment failure and the need to use increasing amounts of the prophylactic drug Isometamidium chloride (ISM) more frequently, suggesting emerging resistance. This project aims to answer the central hypothesis, that the management of animal trypanosomiasis in Tanzania is threatened by an emerging failure of ISM to provide adequate prophylaxis. To test this hypothesis, we will address four main research questions:

1. What are the likely mechanisms by which resistance to ISM occurs and can we identify a marker?
2. What is the extent and cause of ISM failure?
3. What are the epidemiological consequences of ISM failure?
4. How might resistance to trypanocides, including new drugs, be prevented?

Working with researchers from the Tanzanian Veterinary Laboratories Agency, the University of Glasgow and the Roslin Institute at the University of Edinburgh, we will:

1. Identify ISM resistance mechanisms by generating resistant parasites in the laboratory and comparing resistant and susceptible parasites using biochemical, molecular and genomic analysis;

2. Collect field data in the same area in order to assess drug use and drug quality, isolate drug resistant parasites, and assess the epidemiology of drug use and drug resistance in the field;

3. Produce a mathematical model(/or models) using parameters informed by both the laboratory and field data, allowing us to accurately assess how resistance emerges and spreads in AAT in the field; and

4. Apply the model and predict scenarios that will inform on the selection and spread of resistance for a new trypanocidal compound in development by our industrial partners, GALVmed.

LSTM scientists are carrying out laboratory- (Isabel Saldanha) and field-based (Steve Torr) studies of the transmission of susceptible and resistant strains of trypanosome and contributing to the development of mathematical models of trypanosome transmission (Jennifer Lord).

The outputs of this project will provide unprecedented insight into the epidemiology of AAT drug resistance and uncover mechanisms of drug resistance in the disease-relevant trypanosome species, including identification of potential resistance markers. We will also develop the first application of mathematical modelling to provide insights into the dynamics of AAT drug resistance emergence and spread.

The outputs will inform drug development and usage, by identifying strategies that will have the best chances of mitigating resistance, and therefore maximising the lifetime of both existing and novel drugs.