title: Thiolactomycin analogues as potential anti-Toxoplasma gondii agents.
abstract: 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 II 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-MK(2) cells. The TLM analogues demonstrated anti-T. gondii activity, arresting tachyzoite proliferation with IC(50) values in the micromolar level after 24 h and 48 h of treatment. Metabolic labelling of extracellular parasites treated with TLM analogues using [(3)H]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.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Erica S
authors.initials: ES
authors.lastname: Martins-Duarte
authors.forename: Simon M
authors.initials: SM
authors.lastname: Jones
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Georgia C
authors.initials: GC
authors.lastname: Atella
authors.forename: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.forename: Rossiane C
authors.initials: RC
authors.lastname: Vommaro
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000096:biosynthesis*; D005989:Glycerides / Q000096:biosynthesis; D020128:Inhibitory Concentration 50; D046529:Microscopy, Electron, Transmission; D021261:Parasitic Sensitivity Tests; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure
chemical_list: D005227:Fatty Acids; D005989:Glycerides; D013876:Thiophenes; C035068:thiolactomycin