INTRACELLULAR AND FREE FORMS OF TRYPANOSOMATIDS ARE SENSITIVE TO A SOLANESYL DIPHOSPHATE SYNTHASE INHIBITING BISPHOSPHONATE

ESTEBAN J BONTEMPI; NICOLÁS TOMASINI; OCTAVIO FUSCO; ALINA PERRONE; PATRICIA GARAVAGLIA; BRUNO TRAVI; JUAN C ENGEL; BENOIT VANHOLLEBEKE; LAURA E FICHERA; CRISTINA MAIDANA; GABRIELA GARCÍA; JACQUELINE E BÚA; JUAN B RODRÍGUEZ; MÓNICA I ESTEVA; CARLOS PRAVIA; PATRICIO DIOSQUE

Mar del Plata

Congreso; X Congreso de Protozoología y Enfermedades Parasitarias; 2014

Sociedad Argentina Protozoología y Enfermedades Parasitarias

We have previously described that Trypanosoma cruzi and Trypanosoma brucei solanesyl pyrophosphate synthases can be inhibited by 1-[(n-oct-1-ylamino)ethyl] 1,1-bisphosphonic acid (Compound 1) (Ferella 2006, Szajnman 2008, Lai 2014). In T. brucei (Tb) Compound 1 showed metabolic effects similar to those displayed when inhibiting the enzyme or interfering with its expression (Lai 2014). We herein report that insect, bloodstream and intracellular forms of several pathogenic species of trypanosomatids are also sensitive to Compound 1. We found the following EC50s (in microM): T.b.brucei 2, T.b.rhodesiense 0.92 and T.b.gambiense 0.78 (bloodstream forms), L.donovani 200 (promastigote form), L.major >10 and L.donovani 3.3 (amastigote forms), T.cruzi 3.13 (amastigote form). Based on the detection of amino acid differences in several T. cruzi strains, a detailed analysis was carried out to analyze the gene philogeny in the six DTUs and to detect strain variation in drug sensitivities. Although encouraging, the in vitro and ex vivo effectivity of this ?universal? trypanosomatid inhibitor by no means minimizes the need for in vivo experimentation. The tissue distribution of these different human pathogens, either extracellular in the bloodstream or intracellular in different organs, poses special challenges for efficient drug delivery