Abstract African animal trypanosomosis poses a significant threat to livestock health and agricultural productivity across sub-Saharan Africa. Isometamidium chloride is the only available drug that is both prophylactic and curative. Despite sustained reports of resistance since the 1970s, a definitive molecular mechanism of resistance remains unresolved in the clinically relevant pathogen species Trypanosoma congolense . In this study, the role of a putative drug/metabolite transporter protein, TcoDMT, was validated via the analysis of in vitro-derived mutants, showing that expression levels of this protein correlated strongly with isometamidium sensitivity. Functional analyses revealed that the protein is a cell surface phenanthridine transporter and, notably, copy number variation correlates with isometamidium sensitivity in T. congolense field isolates. This study validates, for the first time, a plasma membrane transporter with a defined role in phenanthridine action and resistance, advancing our understanding of drug resistance mechanisms in parasitic protists, and informing strategies to combat animal trypanosomosis.
Steketee et al. (Sat,) studied this question.