Details

Autor(en) / Beteiligte

• Thomas, James A
• Baker, Nicola
• Hutchinson, Sebastian
• Dominicus, Caia
• Trenaman, Anna
• Glover, Lucy
• Alsford, Sam
• Horn, David
• Clos, Joachim

Titel

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

Ist Teil von

• PLoS neglected tropical diseases, 2018-11, Vol.12 (11), p.e0006980

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.