Insights into antitrypanosomal drug mode-of-action from cytology-based profiling

James Thomas, Nicola Baker, Caia Dominicus, Anna Trenaman, Lucy Glover, Sam Alsford, David Horn (Lead / Corresponding author)

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Abstract

Chemotherapy continues to have a major impact on reducing the burden of disease caused by trypanosomatids. Unfortunately though, the mode-of-action (MoA) of antitrypanosomal drugs typically remains unclear or only partially characterised. This is the case for four of five current drugs used to treat Human African Trypanosomiasis (HAT); eflornithine is a specific inhibitor of ornithine decarboxylase. Here, we used a panel of T. brucei cellular assays to probe the MoA of the current HAT drugs. The assays included DNA-staining followed by microscopy and quantitative image analysis, or flow cytometry; terminal dUTP nick end labelling to monitor mitochondrial (kinetoplast) DNA replication; antibody-based detection of sites of nuclear DNA damage; and fluorescent dye-staining of mitochondria or lysosomes. We found that melarsoprol inhibited mitosis; nifurtimox reduced mitochondrial protein abundance; pentamidine triggered progressive loss of kinetoplast DNA and disruption of mitochondrial membrane potential; and suramin inhibited cytokinesis. Thus, current antitrypanosomal drugs perturb distinct and specific cellular compartments, structures or cell cycle phases. Further exploiting the findings, we show that putative mitogen-activated protein-kinases contribute to the melarsoprol-induced mitotic defect, reminiscent of the mitotic arrest associated signalling cascade triggered by arsenicals in mammalian cells, used to treat leukaemia. Thus, cytology-based profiling can rapidly yield novel insight into
antitrypanosomal drug MoA.
Original languageEnglish
Article numbere0006980
Pages (from-to)1-19
Number of pages19
JournalPLoS Neglected Tropical Diseases
Volume12
Issue number11
DOIs
Publication statusPublished - 26 Nov 2018

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Keywords

  • Cell cycle
  • DNA-binding
  • sleeping sickness;
  • Trypanosoma brucei

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