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Mefloquine interferes with glycolysis in schistosomula of Schistosoma mansoni via inhibition of enolase

Published online by Cambridge University Press:  06 February 2012

THERESIA MANNECK ,
JENNIFER KEISER  and
JOACHIM MÜLLER
THERESIA MANNECK
Affiliation:
Department of Medical Parasitology and Infection Biology, Socinstrasse 57, Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland
JENNIFER KEISER*
Affiliation:
Department of Medical Parasitology and Infection Biology, Socinstrasse 57, Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland
JOACHIM MÜLLER
Affiliation:
Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland
*
*Corresponding author: Department of Medical Parasitology and Infection Biology, Socinstrasse 57, Swiss Tropical and Public Health Institute, CH-4051 Basel, Switzerland. Tel: +41 61 284 8218. Fax: +41 61 284 8105. E-mail: jennifer.keiser@unibas.ch
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Summary

The antimalarial drug mefloquine has promising antischistosomal properties killing haematophagous adult schistosomes as well as schistosomula. The mode of action and involved drug targets of mefloquine in Schistosoma mansoni schistosomula are unknown. In order to identify mefloquine-binding proteins and thus potential drug targets, mefloquine affinity chromatography with S. mansoni schistosomula crude extracts was performed. We found one specific mefloquine-binding protein that was identified by mass spectrometry as the glycolytic enzyme enolase (Q27877). Enolase activity assays were performed on schistosomula crude extracts and on the recombinant enolase Q27877 expressed in Escherichia coli. In schistosomula crude extracts enolase activity was inhibited by mefloquine and by the enolase inhibitor sodium fluoride, while activity of the recombinant enolase was not affected. In contrast to enolase from crude extracts, recombinant Q27877 did not bind to mefloquine-agarose. Using isothermal microcalorimetry, we next investigated the metabolic inhibition of mefloquine and 3 known glycolytic inhibitors in Schistosoma spp., namely sodium fluoride, 3-bromopyruvate and menadione on schistosomula in the presence or absence of glucose. We found that in the presence of glucose, schistosomula were less affected by mefloquine, sodium fluoride and 3-bromopyruvate, whereas glucose had no protective effect when schistosomula had been exposed to menadione. These results suggest a potential role of mefloquine as an inhibitor of glycolysis, at least in stages where other targets like haem degradation are not relevant.

Keywords

Schistosoma mansoniaffinity chromatographymefloquinedrug targetenolasemetabolic inhibitionisothermal microcalorimetryglycolysis
Type
Research Article
Information
Parasitology , Volume 139 , Issue 4 , April 2012 , pp. 497 - 505
Copyright
Copyright © Cambridge University Press 2012

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