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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Rossi, Diego Conrado Pereira ; Spadari, Cristina de Castro ; Nosanchuk, Joshua Daniel ; Taborda, Carlos Pelleschi ; Ishida, Kelly
Total Authors: 5
Document type: Journal article
Source: INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS; v. 49, n. 4, p. 465-471, APR 2017.
Web of Science Citations: 8
Abstract

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)

FAPESP's process: 15/07993-0 - ENCAPSULATION OF MILTEFOSINE INTO MICROPARTICLES OF ALGINATE AND EVALUATION OF EFFECTS "IN VITRO" AND "IN VIVO" ON MURINE MODEL OF PULMONARY CRYPTOCOCCOSIS
Grantee:Kelly Ishida
Support Opportunities: Regular Research Grants