Combination with tomatidine improves the potency of posaconazole against Trypanosoma cruzi

Rocha-Hasler, M. and de Oliveira, G. M. and da Gama, A. N. and Fiuza, L. F. A. and Fesser, A. F. and Cal, M. and Rocchetti, R. and Peres, R. B. and Guan, X. L. and Kaiser, M. and Soeiro, M. N. C. and Mäser, P.. (2021) Combination with tomatidine improves the potency of posaconazole against Trypanosoma cruzi. Front Cell Infect Microbiol, 11. p. 617917.

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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 of T. cruzi cytochrome CYP51, the target of azoles, does not deliver sterile cure in monotherapy. Looking for suitable combination partners of azoles, we have selected a set of inhibitors of sterol and sphingolipid biosynthetic enzymes. A small-scale phenotypic screening was conducted in vitro against the proliferative forms of T. cruzi, extracellular epimastigotes and intracellular amastigotes. Against the intracellular, clinically relevant forms, four out of 15 tested compounds presented higher or equal activity as benznidazole (Bz), with EC50 values </=2.2 muM. Ro48-8071, an inhibitor of lanosterol synthase (ERG7), and the steroidal alkaloid tomatidine (TH), an inhibitor of C-24 sterol methyltransferase (ERG6), exhibited the highest potency and selectivity indices (SI = 12 and 115, respectively). Both were directed to combinatory assays using fixed-ratio protocols with Posa, Bz, and fexinidazole. The combination of TH with Posa displayed a synergistic profile against amastigotes, with a mean SigmaFICI value of 0.2. In vivo assays using an acute mouse model of T. cruzi infection demonstrated lack of antiparasitic activity of TH alone in doses ranging from 0.5 to 5 mg/kg. As observed in vitro, the best combo proportion in vivo was the ratio 3 TH:1 Posa. The combination of Posa at 1.25 mpk plus TH at 3.75 mpk displayed suppression of peak parasitemia of 80% and a survival rate of 60% in the acute infection model, as compared to 20% survival for Posa at 1.25 mpk alone and 40% for Posa at 10 mpk alone. These initial results indicate a potential for the combination of posaconazole with tomatidine against T. cruzi.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Fesser, Anna Frieda and Cal, Monica and Rocchetti, Romina and Kaiser, Marcel and Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:2235-2988 (Electronic)2235-2988 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Dec 2022 14:58
Deposited On:20 Dec 2022 14:58

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