Thiolactomycin analogues as potential anti-Toxoplasma gondii agents

The discovery of new compounds active against Toxoplasma gondii is extremely important due to the severe disease caused by this pathogen in immunocompromised hosts and to congenital infection. Type 11 fatty acid biosynthesis has shown to be a promising target for drug intervention in toxoplasmosis. Here we describe the inhibitory effect of 8 thiolactomycin (TLM) analogues against tachyzoite-infected LLC-MK2 cells. The TLM analogues demonstrated anti-T. gondii activity, arresting tachyzoite proliferation with IC50 values in the micromolar level after 24 h and 48 h of treatment. Metabolic labelling of extracellular parasites treated with TLM analogues using [H-3]acetate demonstrated that these drugs affected acylglycerol synthesis. The rapid reduction of parasite load suggests that these compounds have selective cytotoxic effects against T gondii. Transmission electron microscopy demonstrated that TLM analogues interfered with membrane-bounded organelles and parasite division and this in turn affected parasite development and survival. (C) 2009 Elsevier Ireland Ltd. All rights reserved.