title: Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole.
abstract: Sporotrichosis is a common mycosis caused by dimorphic fungi from the Sporothrix schenckii complex. In recent years, sporotrichosis incidence rates have increased in the Brazilian state of Rio de Janeiro, where Sporothrix brasiliensis is the species more frequently isolated from patients. The standard antifungals itraconazole and amphotericin B are recommended as first-line therapy for cutaneous/lymphocutaneous and disseminated sporotrichosis, respectively, although decreased sensitivity to these drugs in vitro was reported for clinical isolates of S. brasiliensis. Here, we evaluated the activity of the phospholipid analogue miltefosine - already in clinical use against leishmaniasis - towards the pathogenic yeast form of S. brasiliensis isolates with low sensitivity to itraconazole or amphotericin B in vitro. Miltefosine had fungicidal activity, with minimum inhibitory concentration (MIC) values of 1-2 µg ml(-1). Miltefosine exposure led to loss of plasma membrane integrity, and transmission electron microscopy (TEM) analysis revealed a decrease in cytoplasmic electron density, alterations in the thickness of cell wall layers and accumulation of an electron-dense material in the cell wall. Flow cytometry analysis using an anti-melanin antibody revealed an increase in cell wall melanin in yeasts treated with miltefosine, when compared with control cells. The cytotoxicity of miltefosine was comparable to those of amphotericin B, but miltefosine showed a higher selectivity index towards the fungus. Our results suggest that miltefosine could be an effective alternative for the treatment of S. brasiliensis sporotrichosis, when standard treatment fails. Nevertheless, in vivo studies are required to confirm the antifungal potential of miltefosine for the treatment of sporotrichosis.
authors: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Luana Pereira
authors: LP
authors: Borba-Santos
authors: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Thalita
authors: T
authors: Gagini
authors: Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors: Kelly
authors: K
authors: Ishida
authors: Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.|Instituto Nacional de Metrologia, Qualidade e Tecnologia, Inmetro, Duque de Caxias, Brazil.
authors: Wanderley
authors: W
authors: de Souza
authors: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Sonia
authors: S
authors: Rozental
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001938:Brazil; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D002473:Cell Wall / Q000187:drug effects / Q000648:ultrastructure; D003593:Cytoplasm / Q000187:drug effects / Q000648:ultrastructure; D025141:Drug Resistance, Fungal; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology* / Q000633:toxicity; D008253:Macaca mulatta; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D013175:Sporothrix / Q000187:drug effects* / Q000302:isolation & purification / Q000648:ultrastructure; D013174:Sporotrichosis / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D010767:Phosphorylcholine; D017964:Itraconazole; C039128:miltefosine; D000666:Amphotericin B