Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi

Azoles such as posaconazole (Posa) are highly potent against Trypanosoma cruzi . However, when tested in chronic Chagas disease patients, a high rate of relapse after Posa treatment was observed. It appears that inhibition T. cytochrome CYP51, the target azoles, does not deliver sterile cure monotherapy. Looking for suitable combination partners we have selected set inhibitors sterol and sphingolipid biosynthetic enzymes. A small-scale phenotypic screening conducted vitro proliferative forms , extracellular epimastigotes intracellular amastigotes. Against intracellular, clinically relevant forms, four out 15 compounds presented higher or equal activity benznidazole (Bz), with EC 50 values ≤2.2 μM. Ro48-8071, an inhibitor lanosterol synthase (ERG7), steroidal alkaloid tomatidine (TH), C-24 methyltransferase (ERG6), exhibited highest potency selectivity indices (SI = 12 115, respectively). Both were directed to combinatory assays using fixed-ratio protocols Posa, Bz, fexinidazole. The TH displayed synergistic profile amastigotes, mean ΣFICI value 0.2. In vivo acute mouse model infection demonstrated lack antiparasitic alone doses ranging from 0.5 5 mg/kg. As observed best combo proportion ratio 3 TH:1 Posa. at 1.25 mpk plus 3.75 suppression peak parasitemia 80% survival 60% model, compared 20% 40% 10 alone. These initial results indicate potential