Host cells participate in the in vitro effects of new-generation diamidine-analogues

Antimicrob Agents Chemother. 2008 Mar 24 [Epub ahead of print]

Host cells participate in the in vitro effects of new-generation diamidine-analogues against tachyzoites of the intracellular apicomplexan parasites Neospora caninum and Toxoplasma gondii

Leepin A, Stüdli A, Brun R, Stephens CE, Boykin DW, Hemphill A.

Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland; Swiss Tropical Institute, Antiparasite Chemotherapy, Socinstrasse 57, CH-4002 Basel, Switzerland; Department of Chemistry, Georgia State University, PO Box 4098, Atlanta, Georgia 30302-4098, USA.

The in vitro effects of 19 dicationic diamidine-derivatives against the proliferative tachyzoite stages of the apicomplexan parasites Neospora caninum and Toxoplasma gondii were investigated. Four compounds (DB811, DB786, DB750 and DB766) with similar structural properties exhibited profound inhibition of tachyzoite proliferation. The lowest IC50 values were noted for DB786 (Neospora-IC50 = 0.21microM; Toxoplasma-IC50 = 0.22microM) and DB750 (Neospora-IC50 = 0.23microM; Toxoplasma-IC50 = 0.16microM), with complete proliferation inhibition at 1.7microM for both drugs in both species. DB750 and DB786 were chosen for further studies. Electron microscopy of N. caninum-infected HFF cultures revealed distinct alterations and damage of parasite ultrastructure upon drug treatment, while host cells remained unaffected. To exert true parasiticidal efficacy against N. caninum, a treatment duration of 3 h at 1.7microM was sufficient for DB750, while a longer treatment period (24 h) was necessary for DB786. Pretreatment of tachyzoites for 1 h prior to host cell exposure had no effect on infectivity. However, pretreatment of uninfected host cells had a significant adverse effect on N. caninum proliferation: exposure of HFF to 1,7microM DB750 for 6, 12 and 24 h, respectively, followed by infection with N. caninum tachyzoites and subsequent culture in the absence of DB750, resulted in a significantly delayed parasite proliferation. This suggests that either these compounds or respective active metabolites were still present after removal of the drugs, or that drug treatments reversably impaired some functional activities in HFF, which were essential for parasite proliferation and/or survival.

PMID: 18362190 [PubMed - as supplied by publisher]