title: Ultrastructural alterations induced by Δ(24(25))-sterol methyltransferase inhibitors on Trichomonas vaginalis.
abstract: Trichomonas vaginalis is an important human parasite that causes trichomoniasis, a cosmopolitan sexually transmitted disease. Currently, the treatment of choice for T. vaginalis infections is metronidazole. The increase in metronidazole-resistant parasites and undesirable side effects of this drug make the search for alternative chemotherapeutic approaches a priority for the management of trichomoniasis. Here, the antiproliferative and ultrastructural effects of sterol biosynthesis inhibitors against T. vaginalis were investigated. It was found that 22,26-azasterol (5 μM) and 24(R,S),25-epiminolanosterol (10 μM), known inhibitors of Δ(24(25))-sterol methyltransferase, exhibited antiproliferative effects on T. vaginalis trophozoites cultured in vitro. Morphological analyses showed that azasterols induced changes in the ultrastructure of T. vaginalis. The most significant alterations were (1) membrane blebbing and disruption, (2) wrinkled cells and (3) the formation of cell clusters. In addition, autophagic vacuoles, Golgi duplication arrest, an abnormal Golgi enlargement and damaged hydrogenosomes were also observed. Nonspecific cytotoxicity assays using the cultured mammalian cell lines Madin-Darby canine kidney cells showed no effect of the azasterols on the viability and proliferation of these cells at a concentration that significantly inhibited the proliferation of T. vaginalis, indicating a selective antiparasitic action. Taken together, these results suggest that azasterols could be important compounds in the development of novel chemotherapeutic approaches against T. vaginalis.
authors.affiliation: Universidade Santa Úrsula, Rio de Janeiro, RJ, Brazil.
authors.forename: Ivone de Andrade
authors.initials: Ide A
authors.lastname: Rosa
authors.forename: Débora Afonso Silva
authors.initials: DA
authors.lastname: Rocha
authors.forename: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.forename: Marlene
authors.initials: M
authors.lastname: Benchimol
mesh_terms: D000818:Animals; D000994:Antitrichomonal Agents / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004083:Cholestanol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D021261:Parasitic Sensitivity Tests; D018675:Toxicity Tests; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000648:ultrastructure*
chemical_list: C103731:22,26-azasterol; D000994:Antitrichomonal Agents; D004791:Enzyme Inhibitors; C059162:24,25-iminolanosterol; D007810:Lanosterol; D004083:Cholestanol; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase