Drug-resistant pathogens emerge faster than new drugs come out of drug discovery pipelines. Current and future drug options should therefore be better protected, requiring a clear understanding of the factors that contribute to the natural history of drug resistance. Although many of these factors are relatively well understood for most bacteria, this proves to be more complex for vectorborne parasites. In this review, we discuss considering three key models (Plasmodium, Leishmania and Schistosoma) how drug resistance can emerge, spread and persist. We demonstrate a multiplicity of scenarios, clearly resulting from the biological diversity of the different organisms, but also from the different modes of action of the drugs used, the specific within- and between-host ecology of the parasites, and environmental factors that may have direct or indirect effects. We conclude that integrated control of drug-resistant vectorborne parasites is not dependent upon chemotherapy only, but also requires a better insight into the ecology of these parasites and how their transmission can be impaired. This review demonstrates the multiplicity of scenarios that occur during the natural history of drug resistance in vectorborne parasites, which not only result from the biological diversity of the different organisms (such as their genome organisation, reproduction mode and life-cycle characteristics), but also from the different modes of action of the drugs used (targeting vulnerable points of their metabolism or key natural defences of the pathogens and thus further boosting pre-existing adaptations), their own specific within- and between-host ecology and environmental factors acting directly (e.g. chemical pollution) or indirectly (through an effect on transmission) on the parasites.
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