Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies

Abstract

Animal trypanosomiasis (AT) is a complex of veterinary diseases known under various names such as nagana, surra, dourine and mal de caderas, depending on the country, the infecting trypanosome species and the host. AT is caused by parasites of the genus Trypanosoma, and the main species infecting domesticated animals are T. brucei brucei, T. b. rhodesiense, T. congolense, T. simiae, T. vivax, T. evansi and T. equiperdum. AT transmission, again depending on species, is through tsetse flies or common Stomoxys and tabanid flies or through copulation. Therefore, the geographical spread of all forms of AT together is not restricted to the habitat of a single vector like the tsetse fly and currently includes almost all of Africa, and most of South America and Asia. The disease is a threat to millions of companion and farm animals in these regions, creating a financial burden in the billions of dollars to developing economies as well as serious impacts on livestock rearing and food production. Despite the scale of these impacts, control of AT is neglected and under-resourced, with diagnosis and treatments being woefully inadequate and not improving for decades. As a result, neither the incidence of the disease, nor the effectiveness of treatment is documented in most endemic countries, although it is clear that there are serious issues of resistance to the few old drugs that are available. In this review we particularly look at the drugs, their application to the various forms of AT, and their mechanisms of action and resistance. We also discuss the spread of veterinary trypanocide resistance and its drivers, and highlight current and future strategies to combat it.

Graphical abstract

Fig. 1

Illustration of drug action and resistance mechanisms in trypanosomes. A. Drug importer such as P2/AT1 transporter for diamidines. B. Drug efflux pump such as multidrug resistance-associated protein (MRAP) in resistance to melaminophenyl arsenicals. C. Mechanisms that relate to delivery and accumulation in or efflux of drug from target organelle such as mitochondrion which houses the kinetoplast, which in itself is a target of multiple trypanocides. E. Surface binding protein, endocytic mechanism or a transporter that delivers endocytosed drug to the cell membrane such as a lysosomal transporter in suramin action. F. Target organelle or molecule that drug binds to. Disruption of these drug transport or action mechanisms may result in drug resistance.

Fig. 2

Structures of synthalin and the main diamidine drugs against trypanosomiasis.

Fig. 2

Structures of synthalin and the main diamidine drugs against trypanosomiasis.

Fig. 3

Structures of an early flavin trypanocide, trypaflavine, and the phenanthridine drugs that were developed therefrom.

Fig. 4

Structures of the main constituents of commercial isometamidium (Samorin). ISM, isometamidium, generally believed to be the (most) active agent in the mixture. The original May & Baker numbers are given.

Fig. 5

Structure of suramin and the early trypanocidal dyes from which suramin was ultimately developed.

Fig. 6

Structures of some of the arsenical drugs that have been (21, 22) or are still used against trypanosomiasis (23, 24). M, melaminophenyl group. BAL, British anti-Lewisite (dimercaprol).

Fig. 7

Structure of quinapyramine.

Fig. 8

Structures of two oxaboroles proposed as veterinary trypanocides.