Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form

Antimicrob Agents Chemother. 2010 Aug 16. [Epub ahead of print]

Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form and study of new derivative compounds

Maubon D, Bougdour A, Wong YS, Brenier-Pinchart MP, Curt A, Hakimi MA, Pelloux H.

Parasitology-Mycology Laboratory, Département des Agents Infectieux, Centre Hospitalier Universitaire, BP 217, 38043 Grenoble, cedex 09, France; UMR 5163, Laboratoire Adaptation et Pathogénie des Micro-organismes, ATIP+ group, CNRS-Université Joseph Fourier GRENOBLE 1, BP 170, F-38042 Grenoble cedex 9, France; Département de Pharmacochimie Moléculaire, Université de Grenoble, CNRS UMR 5063, CNRS ICMG FR 2607, Bâtiment E, 470 Rue de la Chimie, F-38 041 Grenoble cedex 9, France.

Abstract
Bradyzoite to tachyzoite conversion plays a role in pathogenesis of recrudescence of ocular toxoplasmosis and disease in immune compromised persons. The currently available medicines are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. A previous paper showed that the histone deacetylase inhibitor FR235222 has a dramatic effect on tachyzoite growth and induces tachyzoite-to-bradyzoite conversion in vitro. This study shows that FR235222 can target in vitro converted cysts and bradyzoites. Moreover, the compound is active on ex vivo T. gondii cysts. Free bradyzoites isolated after lysis of the cell wall did not proliferate in vitro when the cyst was treated with FR235222. The results imply that this compound is able to cross the T. gondii cystic cell wall. Fluorescent labeling shows that the compound impairs the capacity of the bradyzoites to convert without damaging the cyst wall integrity. In vivo inoculation of formerly treated cysts fails to infect mice when these cysts were treated with FR235222. We used our structural knowledge of FR235222 and its target TgHDAC3 to synthesize new FR235222 derivative compounds. We identified two new molecules that are highly active against tachyzoites. They harbor a better selectivity index that is more suitable for a future in vivo approach in mice with chronic toxoplasmosis. These results identify FR235222 and its derivatives as new lead compounds in the range of therapeutics available in acute and chronic toxoplasmosis.

PMID: 20713670 [PubMed - as supplied by publisher]