TY - JOUR
T1 - In vitro effects of new artemisinin derivatives in Neospora caninum-infected human fibroblasts
AU - Müller, Joachim
AU - Balmer, Vreni
AU - Winzer, Pablo
AU - Rahman, Mahbubur
AU - Manser, Vera
AU - Haynes, Richard K.
AU - Hemphill, Andrew
N1 - Funding Information:
This work was financed through the Swiss National Science Foundation [No. 310030_146162/1 ]. RKH acknowledges funding from the South African Medical Research Council (MRC) with funds from National Treasury under its Economic Competitiveness and Support Package.
Publisher Copyright:
© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
PY - 2015
Y1 - 2015
N2 - From a panel of 34 artemisinin derivatives tested in vitro, artemisone, GC007 and GC012 were most efficacious at inhibiting Neospora caninum replication (IC50 values of 3-54 nM), did not notably impair the invasiveness of tachyzoites and were non-toxic for human foreskin fibroblasts (HFFs). Transmission electron microscopy of drug-treated N. caninum-infected HFFs demonstrated severe alterations in the parasite cytoplasm, changes in the composition of the matrix of the parasitophorous vacuole (PV) and diminished integrity of the PV membrane. To exert parasiticidal activity, parasites had to be cultured continuously in the presence of 5 μM artemisone or GC007 for 3 weeks. N. caninum tachyzoites readily adapted to a stepwise increase in concentrations (0.5-10 (xM) of GC012, but not to artemisone or GC007. Drugs induced the expression of elevated levels of NcBAG1 and NcSAG4 mRNA, but only NcBAG1 could be detected by immunofluorescence. Thus, artemisinin derivatives represent interesting leads that should be investigated further.
AB - From a panel of 34 artemisinin derivatives tested in vitro, artemisone, GC007 and GC012 were most efficacious at inhibiting Neospora caninum replication (IC50 values of 3-54 nM), did not notably impair the invasiveness of tachyzoites and were non-toxic for human foreskin fibroblasts (HFFs). Transmission electron microscopy of drug-treated N. caninum-infected HFFs demonstrated severe alterations in the parasite cytoplasm, changes in the composition of the matrix of the parasitophorous vacuole (PV) and diminished integrity of the PV membrane. To exert parasiticidal activity, parasites had to be cultured continuously in the presence of 5 μM artemisone or GC007 for 3 weeks. N. caninum tachyzoites readily adapted to a stepwise increase in concentrations (0.5-10 (xM) of GC012, but not to artemisone or GC007. Drugs induced the expression of elevated levels of NcBAG1 and NcSAG4 mRNA, but only NcBAG1 could be detected by immunofluorescence. Thus, artemisinin derivatives represent interesting leads that should be investigated further.
KW - Artemisinin
KW - Artemisone
KW - Chemotherapy
KW - Neospora caninum
KW - Resistance
KW - Trioxolane
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U2 - 10.1016/j.ijantimicag.2015.02.020
DO - 10.1016/j.ijantimicag.2015.02.020
M3 - Article
C2 - 25934265
AN - SCOPUS:84935027733
SN - 0924-8579
VL - 46
SP - 88
EP - 93
JO - International Journal of Antimicrobial Agents
JF - International Journal of Antimicrobial Agents
IS - 1
ER -
