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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 µg/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 µg/mL. Ultrastructural alterations were observed following exposure of the fungus to a subinhibitory concentration of MLT, such as cytoplasmic membrane alteration, mitochondrial swelling, electron-lucent vacuole accumulation and increasing melanosome-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.

Original languageEnglish (US)
Pages (from-to)465-471
Number of pages7
JournalInternational Journal of Antimicrobial Agents
Volume49
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

miltefosine
Paracoccidioides
Yeasts
Melanins
Paracoccidioidomycosis
Fungi
Mitochondrial Swelling
Melanosomes
Itraconazole
Mycoses
Sulfamethoxazole Drug Combination Trimethoprim
Amphotericin B

Keywords

  • Antifungal
  • Melanin
  • Miltefosine
  • Paracoccidioides

ASJC Scopus subject areas

  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Miltefosine is fungicidal to Paracoccidioides spp. yeast cells but subinhibitory concentrations induce melanisation. / Rossi, Diego Conrado Pereira; Spadari, Cristina de Castro; Nosanchuk, Joshua D.; Taborda, Carlos Pelleschi; Ishida, Kelly.

In: International Journal of Antimicrobial Agents, Vol. 49, No. 4, 01.04.2017, p. 465-471.

Research output: Contribution to journalArticle

Rossi, Diego Conrado Pereira ; Spadari, Cristina de Castro ; Nosanchuk, Joshua D. ; Taborda, Carlos Pelleschi ; Ishida, Kelly. / Miltefosine is fungicidal to Paracoccidioides spp. yeast cells but subinhibitory concentrations induce melanisation. In: International Journal of Antimicrobial Agents. 2017 ; Vol. 49, No. 4. pp. 465-471.
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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 µg/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 µg/mL. Ultrastructural alterations were observed following exposure of the fungus to a subinhibitory concentration of MLT, such as cytoplasmic membrane alteration, mitochondrial swelling, electron-lucent vacuole accumulation and increasing melanosome-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.",
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