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<p>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 <i>Trypanosoma congolense</i>. 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 <i>T. congolense</i> 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.</p>

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A cell surface transporter mediates phenanthridine resistance in African trypanosomes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月4日

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  • Pieter C. Steketee,
  • Marzuq A. Ungogo,
  • Edith Paxton,
  • Ella Maria Rogerson,
  • Furaha Mramba,
  • Michael C. Pearce,
  • Harriet K. Auty,
  • Jan Van Den Abbeele,
  • Harry P. de Koning,
  • Catarina Gadelha,
  • Michael P. Barrett,
  • Liam J. Morrison

摘要

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.