Reversible paralysis of Schistosoma mansoni by forchlorfenuron, a phenylurea cytokinin that affects septins.

Abstract

Septins are guanosine-5'-triphosphate-binding proteins involved in wide-ranging cellular processes including cytokinesis, vesicle trafficking, membrane remodelling and scaffolds, and with diverse binding partners. Precise roles for these structural proteins in most processes often remain elusive. Identification of small molecules that inhibit septins could aid in elucidating the functions of septins and has become increasingly important, including the description of roles for septins in pathogenic phenomena such as tumorigenesis. The plant growth regulator forchlorfenuron, a synthetic cytokinin known to inhibit septin dynamics, likely represents an informative probe for septin function. This report deals with septins of the human blood fluke Schistosoma mansoni and their interactions with forchlorfenuron. Recombinant forms of three schistosome septins, SmSEPT5, SmSEPT7.2 and SmSEPT10, interacted with forchlorfenuron, leading to rapid polymerization of filaments. Culturing developmental stages (miracidia, cercariae, adult males) of schistosomes in FCF at 50-500 μM rapidly led to paralysis, which was reversible upon removal of the cytokinin. The reversible paralysis was concentration-, time- and developmental stage-dependent. Effects of forchlorfenuron on the cultured schistosomes were monitored by video and/or by an xCELLigence-based assay of motility, which quantified the effect of forchlorfenuron on fluke motility. The findings implicated a mechanism targeting a molecular system controlling movement in these developmental stages: a direct effect on muscle contraction due to septin stabilization might be responsible for the reversible paralysis, since enrichment of septins has been described within the muscles of schistosomes. This study revealed the reversible effect of forchlorfenuron on both schistosome motility and its striking impact in hastening polymerization of septins. These novel findings suggested routes to elucidate roles for septins in this pathogen, and exploitation of derivatives of forchlorfenuron for anti-schistosomal drugs.

• Authors: Ana E Zeraik, Vitold E Galkin, Gabriel Rinaldi, Richard C Garratt, Michael J Smout, Alex Loukas, Victoria H Mann, Ana P U Araujo, Ricardo DeMarco, Paul J Brindley
• Journal: International journal for parasitology (Int J Parasitol) Vol. 44 Issue 8 Pg. 523-31 (Jul 2014) ISSN: 1879-0135 [Electronic] England
• PMID: 24768753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Anthelmintics
• Cytokinins
• Phenylurea Compounds
• Pyridines
• Septins
• N-(2-chloro-4-pyridyl)-N'-phenylurea

Topics

• Animals
• Anthelmintics (pharmacology)
• Cytokinins (pharmacology)
• Paralysis (chemically induced)
• Phenylurea Compounds (pharmacology)
• Pyridines (pharmacology)
• Schistosoma mansoni (drug effects)
• Septins (antagonists & inhibitors)