Miltefosine is fungicidal to Paracoccidioides spp. yeast cells but subinhibitory concentrations induce melanisation

Autor(es)

Rossi, Diego Conrado Pereira ; Spadari, Cristina de Castro ; Nosanchuk, Joshua Daniel ; Taborda, Carlos Pelleschi ; Ishida, Kelly

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS; v. 49, n. 4, p. 465-471, APR 2017.
• Citações Web of Science: 8

Resumo

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the dimorphic fungi Paracoccidioides spp. The duration of antifungal treatment ranges from months to years and relapses may nevertheless occur despite protracted therapy. Thus, there remains an urgent need for new therapeutic options. Miltefosine (MLT), an analogue of alkylphospholipids, has antifungal activity against species of yeast and filamentous fungi. The aim of this study was to evaluate the antifungal effects of MLT on the yeast forms of Paracoccidioides brasiliensis and Paracoccidioides lutzii. MLT demonstrated inhibitory activity from 0.12 to 1 mu g/mL, which was similar to amphotericin B or the combination trimethoprim/sulfamethoxazole but was not more effective than itraconazole. The fungicidal activity of MLT occurred at concentrations >= 1 mu g/mL. Ultrastructural alterations were observed following exposure of the fungus to a subinhibitory concentration of MLT, such as cytoplasmic membrane alteration, mitochondrial swelling, electronlucent vacuole accumulation and increasing melano some-like structures. Melanin production by yeasts following MLT exposure was confirmed by labelling with antibodies to melanin. In addition, the combination of a subinhibitory concentration of MLT and tricyclazole, an inhibitor of DHN-melanin biosynthesis, drastically reduced yeast viability. In conclusion, MLT had a fungicidal effect against both Paracoccidioides spp., and a subinhibitory concentration impacted melanogenesis. These findings suggest that additional investigations should be pursued to establish a role for MLT in the treatment of PCM. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved. (AU)

• Processo FAPESP: 15/07993-0 - Encapsulamento da miltefosina em micropartículas de alginato e avaliação dos efeitos "in vitro" e "in vivo" em modelo murino de criptococose pulmonar
• Beneficiário: Kelly Ishida
• Modalidade de apoio: Auxílio à Pesquisa - Regular