Difernt strains of trypanosoma cruzi present distinct suceptibilities to posaconasole derived drugs?

VANRELL MC; CASASSA AF; HARGROVE TY; LEPESHEVA GI; ROMANO PS

Congreso; SAIB XLVIII Reunión anual; 2012

The use of anti-fungal azoles, which block sterol biosynthesis, against protozoan parasites has turned out to be highly successful. Inhibitors of the trypanosome sterol 14a-demethylase (CYP51) are promising candidates as anti-Chagas disease drugs. In this work we have tested VNI, a compound identified as a potent T. cruzi 14a- demethylase inhibitor (Lepesheva et al , 2010). Our results, analyzing epimastigote and intracellular amastigote growth in T. cruzi Y strain, show that 500 nM and 1 μM VNI affects parasite replication reducing the values around 50 % respects to controls. Trypomastigotes are also affected since a significant reduction in the percentage of infected cells were obtained after VNI treatment. Although these results show an important effect of VNI, similar experiments conducted in other T. cruzi strains revealed a stronger action of this compound. To analyze the origin of these differences, CYP51 gene from Ystrain was cloned and sequenced. Interestingly, in contrast with CYP51s from CL Brener and Tulahuen strains, T. cruzi Y strain has two CYP51 genes (A and B). Chemical and structural differences in these genes could explain the higher resistance of this strain to VNI. This study will serve as the basis to design new, more potent compounds, which we will test in T. cruzi strains and in animal models.