Miltefosine Has a Postantifungal Effect and Induces Apoptosis in Cryptococcus Yeasts

Abstract

spp. are common opportunistic fungal pathogens, particularly in HIV patients. The approved drug miltefosine (MFS) has potential as an alternative antifungal against cryptococcosis; however, the mechanism of action of MFS in is poorly understood. Here, we examined the effects of MFS on and yeasts (planktonic and biofilm lifestyles) to clarify its mechanism of action. MFS presented inhibitory and fungicidal effects against planktonic cells, with similar activities against dispersion biofilm cells, while sessile biofilm cells were less sensitive to MFS. Interestingly, MFS had postantifungal effect on , with a proliferation delay of up to 8.15 h after a short exposure to fungicidal doses. MFS at fungicidal concentrations increased the plasma membrane permeability, likely due to a direct interaction with ergosterol, as suggested by competition assays with exogenous ergosterol. Moreover, MFS reduced the mitochondrial membrane potential, increased reactive oxygen species (ROS) production, and induced DNA fragmentation and condensation, all of which are hallmarks of apoptosis. Transmission electron microscopy analysis showed that MFS-treated yeasts had a reduced mucopolysaccharide capsule (confirmed by morphometry with light microscopy), plasma membrane irregularities, mitochondrial swelling, and a less conspicuous cell wall. Our results suggest that MFS increases the plasma membrane permeability in via an interaction with ergosterol and also affects the mitochondrial membrane, eventually leading to apoptosis, in line with its fungicidal activity. These findings confirm the potential of MFS as an antifungal against and and warrant further studies to establish clinical protocols for MFS use against cryptococcosis.

A Novel Antimicrobial Peptide Scyreprocin From Mud Crab Scylla paramamosain Showing Potent Antifungal and Anti-biofilm Activity

“…Additionally, rScyreprocin had an alternative way to ensure its fungicidal activity by inducing cell apoptosis. This antifungal feature of rScyreprocin was similar to that of miltefosine (Spadari et al, 2018). After rScyreprocin treatment, increased membrane permeability and chromatin condensation of C. albicans were observed.…”

Repositionable Compounds with Antifungal Activity against Multidrug Resistant Candida auris Identified in the Medicines for Malaria Venture’s Pathogen Box

“…Miltefosine has also been used successfully in a limited number of cases of the extremely rare highly lethal brain infection by the amoeba Naegleria fowleri and, in the United States, has orphan drug status for the treatment of other amebic infections [62]. Our group and others have previously described the antifungal activity of miltefosine [63][64][65][66][67][68]. Iodoquinol (also referred to as diiodohydroxyquinoline) is an halogenated quinoline derivative (see Supplementary Figure S1) that is used as an intestinal antiparasitic drug, mainly in the treatment of Entamoeba histolytica infections [69], apparently acting by chelation of ferrous ions essential for metabolism.…”

Nanocarriers Provide Sustained Antifungal Activity for Amphotericin B and Miltefosine in the Topical Treatment of Murine Vaginal Candidiasis

“…Both AMB and MFS have broad spectrum of antifungal activity, fungicidal and post-antifungal effects (Dorlo et al, 2012;Spadari et al, 2018). Importantly, these drugs are effective against Candida spp.…”