Miltefosine Against Scedosporium and Lomentospora Species: Antifungal Activity and Its Effects on Fungal Cells

Abstract

Scedosporium and Lomentospora species are filamentous fungi responsible for a wide range of infections in humans and are frequently associated with cystic fibrosis and immunocompromising conditions. Because they are usually resistant to many antifungal drugs available in clinical settings, studies of alternative targets in fungal cells and therapeutic approaches are necessary. In the present work, we evaluated the in vitro antifungal activity of miltefosine against Scedosporium and Lomentospora species and how this phospholipid analogue affects the fungal cell. Miltefosine inhibited different Scedosporium and Lomentospora species at 2–4 µg/ml and reduced biofilm formation. The loss of membrane integrity in Scedosporium aurantiacum caused by miltefosine was demonstrated by leakage of intracellular components and lipid raft disorganisation. The exogenous addition of glucosylceramide decreased the inhibitory activity of miltefosine. Reactive oxygen species production and mitochondrial activity were also affected by miltefosine, as well as the susceptibility to fluconazole, caspofungin and myoricin. The data obtained in the present study contribute to clarify the dynamics of the interaction between miltefosine and Scedosporium and Lomentospora cells, highlighting its potential use as new antifungal drug in the future.

Sporothrix spp. Biofilms Impact in the Zoonotic Transmission Route: Feline Claws Associated Biofilms, Itraconazole Tolerance, and Potential Repurposing for Miltefosine

“…The mechanism of action related to the antifungal activity of miltefosine is not fully understood; however, it is partly due to the induction of apoptotic-like cell death and increased plasma membrane permeability [27]. Spadari et al, 2018 and Rollin-Pinheiro et al, 2021 showed that miltefosine decreased mitochondrial membrane potential and increased ROS levels in Cryptococcus neoformans and Scedosporium aurantiacum [24,28]. Miltefosine induces pronounced disturbances in the plasma membrane in planktonic Sporothrix cells [13].…”

In Vitro Antifungal Susceptibility Profile of Miltefosine against a Collection of Azole and Echinocandins Resistant Fusarium Strains

“…Although many studies on protozoa have been performed, little is known about the effects of miltefosine in fungi. Miltefosine has been shown to have in vitro antifungal activity against numerous clinically significant molds and yeasts, including dimorphic fungi, Aspergillus spp., Scedosporium spp., Sporothrix spp., Cryptococcus spp., Candida spp., dermatophytes and some of the zygomycetes, although the mechanism of action of this compound in fungi is still poorly understood [ 22 , 23 , 24 , 25 , 26 , 27 ]. Rollin-Pinheiro et al evaluated the in vitro antifungal activity of miltefosine against Scedosporium species and showed that miltefosine affects Scedosporium and Lomentospora species at the early stages of growth and inhibits them at 2–4 μg/mL as well as reducing biofilm formation [ 27 ].…”

“…Miltefosine has been shown to have in vitro antifungal activity against numerous clinically significant molds and yeasts, including dimorphic fungi, Aspergillus spp., Scedosporium spp., Sporothrix spp., Cryptococcus spp., Candida spp., dermatophytes and some of the zygomycetes, although the mechanism of action of this compound in fungi is still poorly understood [ 22 , 23 , 24 , 25 , 26 , 27 ]. Rollin-Pinheiro et al evaluated the in vitro antifungal activity of miltefosine against Scedosporium species and showed that miltefosine affects Scedosporium and Lomentospora species at the early stages of growth and inhibits them at 2–4 μg/mL as well as reducing biofilm formation [ 27 ]. Spadari et al also confirmed that miltefosine has an antifungal effect against Cryptococcus species with MIC values ranging from 0.5 to 2 μg/mL and fungicidal activity by apoptosis [ 39 ].…”

“…However, previous studies have shown that good in vitro effects of miltefosine do not always translate into in vivo efficacy, and miltefosine also works better when combined with other antifungal drugs [ 44 ]. Although miltefosine has in vitro activity against several fungi [ 22 , 23 , 24 , 25 , 26 , 27 , 40 , 41 , 42 , 43 ], there is insufficient evidence of its efficacy in vivo. Our study on Fusarium is in agreement with the above-mentioned studies.…”

“…Miltefosine has been shown to have in vitro activity against numerous clinically significant molds and yeasts including dimorphic fungi, Aspergillus spp., Fusarium spp., Scedosporium spp., Rhizopus spp., dermatophytes, Cryptococcus spp., and Candida spp. [ 22 , 23 , 24 , 25 , 26 , 27 ]. Given the limited data available on miltefosine’s antifungal susceptibility pattern against Fusarium species, we evaluated this agent’s in vitro activity against a variety of Fusarium species.…”