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The adaptive potential of a survival artist: characterization of the in vitro interactions of Toxoplasma gondii tachyzoites with di-cationic compounds in human fibroblast cell cultures

Published online by Cambridge University Press:  19 October 2011

CHRISTIAN KROPF ,
KARIM DEBACHE ,
CHRISTOPH RAMPA ,
FABIENNE BARNA ,
MICHELLE SCHORER ,
CHAD E. STEPHENS ,
MOHAMED A. ISMAIL ,
DAVID W. BOYKIN  and
ANDREW HEMPHILL
CHRISTIAN KROPF
Affiliation:
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland
KARIM DEBACHE
Affiliation:
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland
CHRISTOPH RAMPA
Affiliation:
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland
FABIENNE BARNA
Affiliation:
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland
MICHELLE SCHORER
Affiliation:
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland
CHAD E. STEPHENS
Affiliation:
Department of Chemistry and Physics, Augusta State University, Augusta, Georgia 30904-2200, USA
MOHAMED A. ISMAIL
Affiliation:
Department of Chemistry, Georgia State University, PO Box 4098, Atlanta Georgia, USA Department of Chemistry, College of Science, King Faisal University, PO Box, Hofuf 31982, Saudi Arabia
DAVID W. BOYKIN
Affiliation:
Department of Chemistry, Georgia State University, PO Box 4098, Atlanta Georgia, USA
ANDREW HEMPHILL*
Affiliation:
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland
*
*Corresponding author: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland. Tel: +41 31 631 2384. Fax: +41 31 631 2477. E-mail: andrew.hemphill@vetsuisse.unibe.ch
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Summary

The impact of di-cationic pentamidine-analogues against Toxoplama gondii (Rh- and Me49-background) was investigated. The 72 h-growth assays showed that the arylimidamide DB750 inhibited the proliferation of tachyzoites of T. gondii Rh and T. gondii Me49 with an IC50 of 0·11 and 0·13 μm, respectively. Pre-incubation of fibroblast monolayers with 1 μm DB750 for 12 h and subsequent culture in the absence of the drug also resulted in a pronounced inhibiton of parasite proliferation. However, upon 5–6 days of drug exposure, T. gondii tachyzoites adapted to the compound and resumed proliferation up to a concentration of 1·2 μm. Out of a set of 32 di-cationic compounds screened for in vitro activity against T. gondii, the arylimidamide DB745, exhibiting an IC50 of 0·03 μm and favourable selective toxicity was chosen for further studies. DB745 also inhibited the proliferation of DB750-adapted T. gondii (IC50=0·07 μm). In contrast to DB750, DB745 also had a profound negative impact on extracellular non-adapted T. gondii tachyzoites, but not on DB750-adapted T. gondii. Adaptation of T. gondii to DB745 (up to a concentration of 0·46 μm) was much more difficult to achieve and feasible only over a period of 110 days. In cultures infected with DB750-adapted T. gondii seemingly intact parasites could occasionally be detected by TEM. This illustrates the astonishing capacity of T. gondii tachyzoites to adapt to environmental changes, at least under in vitro conditions, and suggests that DB745 could be an interesting drug candidate for further assessments in appropriate in vivo models.

Keywords

Toxoplasma gondiidi-cationic pentamidine analoguesarylimidamidesproliferationtachyzoitesin vitro models
Type
Research Article
Information
Parasitology , Volume 139 , Issue 2 , February 2012 , pp. 208 - 220
Copyright
Copyright © Cambridge University Press 2011

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