Professor Colin J Suckling explains how teams at the University of Strathclyde and University of Glasgow are challenging global parasitic infection
Cows, horse, camels
When people talk about drug discovery the automatic reaction is to consider human health. In most countries with stable food supplies that are an understandable response. However in countries vulnerable to variable climatic conditions and with limited quality pasture, as is typical of the north and sub-Saharan Africa, food supply from domestic animals is at risk from diseases of cattle in particular. The bovine equivalent of human sleeping sickness in Africa is known as nagana, or Animal African Trypanosomiasis, and is caused by a number of species of parasites of the genus Trypanosoma. Like the human disease, it is also spread by the tsetse fly. Nagana can be devastating to communities dependent upon cattle, even breeds adapted to the African environment.
In more affluent environments around the world, animals at risk of trypanosomal infections are also found. In Arabia and North Africa, camel racing is a hugely popular sport, but both camels and dromedaries are susceptible to trypanosomiasis. Away from the race track, camels are well known to be at the heart of the rural economies in these regions. In South America, another species of trypanosome causes a similar disease in horses, which are also important in rural areas. In both Africa and South America, there are species of trypanosome that affect both humans and animals.
New drugs for old
The old drugs available for treatment are losing their efficacy because of developing resistance in the trypanosome parasite. In any case, the old drugs are unpleasant in use and require prolonged treatment, which in rural African environments are difficult to manage. This is the sadly familiar 21st-century story of antimicrobial resistance, threatening animal and human life and well-being. When we started our anti-infective drug discovery programme at the University of Strathclyde more than 10 years ago, we did not know what the most significant applications might be. Naturally, as I noted above, we started to screen compounds against human bacterial and fungal pathogens but as the scope of our screening expanded, we found with the help of many collaborating laboratories that a subset of our compounds is particularly active against trypanosome parasites.
In addition to the potential economic benefit of new and effective treatments for animal trypanosomiasis, in several parts of the world the range of species of economically important animals that can be affected is surprisingly large. Here’s a short selection of Trypanosoma species with the host animal noted beside brucei, sleeping sickness in humans and nagana in cattle;
- T.cruzi, Chagas disease in humans; also infects cattle and horses;
- T.congolense, nagana in ruminant livestock, horses and a wide range of wildlife;
- T.equinum, in horses;
- T.equiperdum, in horses and other equidae;
- T.evansi, in horses, camels, deer: from Atlantic North Africa right across to Arabian peninsular;
- T.lewisi, in rats;
- T.melophagium, in sheep;
- T.simiae, nagana in pigs;
- T.vivax, nagana in cattle, also infects camels, horses, and antelope.
The Strathclyde and Glasgow programme
With so many infective agents (and there are more) it might be expected that a single new drug would be difficult to find. However, the similarities between the different species of trypanosomes are such that there is a reasonable chance of success. A key test of this point is whether the potential new drug is active against Trypanosoma brucei and closely related species, principally from Africa, and against the relatively distantly related Trypanosoma cruzi, which occurs in South America. Results that arrived just this week (26th June) have prompted me to write this piece, to show convincingly that we can treat both types of trypanosome with our new compounds. This seems to me to be a major advance for our programme. So what can our compounds do?
The first hint that we might have useful compounds came from studies in Michael Barrett’s laboratory at our neighbours, the University of Glasgow. He and his colleagues showed that there was significant activity against the human parasite, T. brucei, and were able to study some features of the mechanism of action. The team went on to show that our compounds were also active against one of the key species that infects cattle, T. congolense, with activity sufficiently high to suggest that development into an effective medicine would be possible. Later, in work being prepared for publication, his team importantly showed that our potential new drugs were effective against strains of parasite resistant to the most used old drugs, pentamidine and diminazine.
In rural Africa, animal infections are commonly caused by either T. congolense or T. vivax or both. To have an effective new drug our compounds would clearly have to be active against both species. Mike’s team was not in a position to screen against T. vivax because the parasite cannot be cultured. We were therefore introduced with the help of the not-for-profit animal and veterinary health company GalvMed, based here in Scotland, to Kirsten Gillingwater at the Swiss Tropical and Public Health Laboratory in Basel. She evaluated our compounds against T. vivax and we were very pleased to find that some were active, from which we selected two for further evaluation, MGB234 and MGB360.
It’s all very well having compounds that work in a laboratory assay but will they cure disease in an animal? Having established that MGB234 and MGB360 were not acutely toxic in mice, Mike Barrett’s team was able to begin to answer this question. Over the last six months we’ve been greatly encouraged by clear evidence from his team’s experiments that MGB360 is able to cure mice of a T. vivax infection at reasonable doses. Also important was that the mice survived the course of treatment and there were no deaths due to drug treatment. MGB360 is just the pilot compound; by making small modifications to its structure we think we have a still better one, MGB402, but time and experiment will tell.
Will MGB360 and its relatives have a sufficient range of effectiveness worldwide? That’s where this week’s results from South America come in. Ariel Silber and his students at the University of São Paulo have just reported to us that MGB402 is very effective at killing the South American species of trypanosome, T. cruzi, which is causes Chagas disease in humans and also infects livestock widely. This means that not only do we have worldwide coverage with our compounds but we also most probably can attack all species in the Trypanosoma genus. In clinical use, therefore, it would not be necessary to identify the species, which would be a great advantage for the farmer working with the veterinarian and for the human clinician. So we’re now working hard to expand the profile of our compounds to find out whether they are genuine candidates for full-scale development towards clinical use. That’s not bad for one small chemistry team.
The place of useful learning
The University of Strathclyde is a charitable body, registered in Scotland, number SC015263
Prof Colin J Suckling OBE DSc FRSE
Research Professor of Chemistry
Department of Pure & Applied Chemistry
University of Strathclyde
Tel: 0141 5482271
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