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. 2011 Apr;49(4):1217-25.
doi: 10.1128/JCM.02382-10. Epub 2011 Jan 26.

Isothermal microcalorimetry to study drugs against Schistosoma mansoni

Theresia Manneck  1 , Olivier Braissant, Yolanda Haggenmüller, Jennifer Keiser
Affiliations

Isothermal microcalorimetry to study drugs against Schistosoma mansoni

Theresia Manneck et al. J Clin Microbiol. 2011 Apr.

Abstract

Alternative antischistosomal drugs are required since praziquantel is virtually the only drug available for treatment and morbidity control of schistosomiasis. Manual microscopic reading is the current "gold standard" to assess the in vitro antischistosomal properties of test drugs; however, it is labor-intensive, subjective, and difficult to standardize. Hence, there is a need to develop novel tools for antischistosomal drug discovery. The in vitro effects of praziquantel, oxamniquine, artesunate, and mefloquine on metabolic activity and parasite motility of Schistosoma mansoni (newly transformed schistosomula [NTS] and 49-day-old adult worms) were studied using isothermal microcalorimetry (IMC). Results were compared to morphological readouts of viability. Results obtained for the four drugs tested with phenotypic evaluation by microscopy and IMC showed a good correlation, but IMC also identified drug effects that were not visible by microscopic evaluation, and IMC precisely determined the onset of action of the test drugs. Similar sensitivities on NTS and adult schistosomes were observed for praziquantel and mefloquine, while slight differences in the drug susceptibilities of the two developmental stages were noted with oxamniquine and artesunate. IMC is a useful tool for antischistosomal drug discovery that should be further validated. In addition, our data support the use of NTS in in vitro antischistosomal drug assays.

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Figures

Fig. 1.
Fig. 1.
Injection system for IMC. 1, microcalorimeter tube; 2, rod with insulating rings; 3, prefilled 0.5-ml syringe (medium/drugs) (Becton Dickinson, NJ); 4, ampoule with schistosomes; 5, thermoelectric module.
Fig. 2.
Fig. 2.
Viability of S. mansoni NTS following in vitro treatment with praziquantel (A), oxamniquine (B), artesunate (C), and mefloquine (D) (100, 10, and 1 μg/ml) over time. Mean values of viability (viability score) were derived from a minimum of 6 experiments.
Fig. 3.
Fig. 3.
Light microscopic observations of S. mansoni NTS after in vitro incubation with 10 μg/ml praziquantel, oxamniquine, and artesunate for 72 h and 10 μg/ml mefloquine for 24 h.
Fig. 4.
Fig. 4.
Viability of adult S. mansoni following in vitro treatment with praziquantel (A), oxamniquine (B), artesunate (C), and mefloquine (D) (100, 10, and 1 μg/ml) over time. Mean values of viability (viability score) were derived from a minimum of 6 experiments.
Fig. 5.
Fig. 5.
In vitro response (viability) of 2 developmental stages of S. mansoni (NTS and adults) to praziquantel, oxamniquine, artesunate, and mefloquine 24 h and 72 h after drug incubation. Asterisk, significant difference between control and drug of interest (P < 0.05).
Fig. 6.
Fig. 6.
Heat-flow curves of S. mansoni NTS exposed to 3 different concentrations of praziquantel, oxamniquine, artesunate, and mefloquine in vitro. Black lines, negative control (untreated NTS); dark gray dotted lines, background control (culture medium); light gray dotted lines, positive control (dead NTS); dark gray lines, 100 μg/ml; medium gray lines, 10 μg/ml; light gray lines, 1 μg/ml. Data shown are mean values from 3 experiments. Arrows indicate the time of medium or drug injection.
Fig. 7.
Fig. 7.
Heat-flow curves of adult S. mansoni worms treated with 3 different concentrations of praziquantel, oxamniquine, artesunate, and mefloquine in vitro. Black lines, negative control (untreated schistosomes); dark gray dotted lines, background control (culture medium); light gray dotted lines, positive control (dead schistosomes); dark gray lines, 100 μg/ml; medium gray lines, 10 μg/ml; light gray lines, 1 μg/ml. Data shown are mean values from 3 experiments. Arrows indicate the time of medium or drug injection.
Fig. 8.
Fig. 8.
In vitro response (heat flow) of two developmental stages of S. mansoni (NTS and adults) to praziquantel, oxamniquine, artesunate, and mefloquine at 24 h and 72 h after drug addition. Asterisk, significant difference between control and drug of interest (P < 0.05).
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