Potent in vitro antiproliferative synergism of combinations of ergosterol biosynthesis inhibitors against Leishmania amazonensis.
Antimicrob Agents Chemother. 2015 Aug 3;
Authors: Macedo-Silva ST, Visbal G, Urbina JA, de Souza W, Rodrigues JC
Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high cost and difficult administration. Thus, there is an urgent need for safer and more effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we have shown that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase and to the azoles itraconazole (ITZ) and posaconazole (POSA) that inhibit C14α-demethylase. Herein, we investigated the antiproliferative, ultrastructural and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentrations (FIC) values of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and plus POSA, respectively. Against amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis.
PMID: 26239973 [PubMed - as supplied by publisher]