Kinetoplastid diseases: Insights into the mechanisms of drug action and resistance for novel drug discovery

Trypanosoma and Leishmania species are kinetoplastid protozoan parasites that cause diseases which result in significant disability-adjusted life years (DALYs) and agricultural losses in the developing world. Despite the progress recorded in understanding biology and chemotherapy of these pathogens of neglected diseases, treatment failure, due to drug resistance or toxicity-driven non-compliance remain major challenges. Advances in molecular parasitology have led to the identification of specific transport mechanisms, druggable targets and persister-like cells, which play distinct roles in the overall success of therapies. Transporters and other cellular transport mechanisms affect the internalization of drugs and their intracellular availability which determine drug activity. Thus, we reviewed kinetoplastid drug transport mechanisms, molecular drug targets and persisters to highlight mechanisms of action and development of resistance for antikinetoplastid drugs, with the aim of providing novel insights for drug discovery programmes. • Transporters and other cellular transport mechanisms affect the internalization of drugs • Drug resistance remains an important challenge to the control of kinetoplastid diseases • Mutations or differential expression in drug efflux pumps contribute to drug resistance • Valuable data on mechanisms of kinetoplastid drug resistance generated • Use of proteins 3D and AlphaFold in rational drug design offers hope of better drugs