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

Christian Kropf, Karim Debache, Christoph Rampa, Fabienne Barna, Michelle Schorer, Chad E. Stephens, Mohamed A. Ismail, David W. Boykin, Andrew Hemphill

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 IC 50 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 IC 50 of 003 μm and favourable selective toxicity was chosen for further studies. DB745 also inhibited the proliferation of DB750-adapted T. gondii (IC 50=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.

Original languageEnglish (US)
Pages (from-to)208-220
Number of pages13
JournalParasitology
Volume139
Issue number2
DOIs
StatePublished - Feb 1 2012

Fingerprint

tachyzoites
Toxoplasma
Toxoplasma gondii
fibroblasts
cell culture
Cell Culture Techniques
Fibroblasts
Survival
inhibitory concentration 50
drugs
Parasites
In Vitro Techniques
Pharmaceutical Preparations
Pentamidine
parasites
toxicity

Keywords

  • Toxoplasma gondii
  • arylimidamides
  • di-cationic pentamidine analogues
  • in vitro models
  • proliferation
  • tachyzoites

ASJC Scopus subject areas

  • Parasitology
  • Animal Science and Zoology
  • Infectious Diseases

Cite this

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. / Kropf, Christian; Debache, Karim; Rampa, Christoph; Barna, Fabienne; Schorer, Michelle; Stephens, Chad E.; Ismail, Mohamed A.; Boykin, David W.; Hemphill, Andrew.

In: Parasitology, Vol. 139, No. 2, 01.02.2012, p. 208-220.

Research output: Contribution to journalArticle

Kropf, Christian ; Debache, Karim ; Rampa, Christoph ; Barna, Fabienne ; Schorer, Michelle ; Stephens, Chad E. ; Ismail, Mohamed A. ; Boykin, David W. ; Hemphill, Andrew. / 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. In: Parasitology. 2012 ; Vol. 139, No. 2. pp. 208-220.
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