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

doi:10.1016/j.ijantimicag.2016.12.020

Cited by 30 publications

(29 citation statements)

References 36 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Wall

Herrera

Lopez-Ribot

2019

JoF

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Background. Candida auris has spread rapidly around the world as a causative agent of invasive candidiasis in health care facilities and there is an urgent need to find new options for treating this emerging, often multidrug-resistant pathogen. Methods. We screened the Pathogen Box® chemical library for inhibitors of C. auris strain 0390, both under planktonic and biofilm growing conditions. Results. The primary screen identified 12 compounds that inhibited at least 60% of biofilm formation or planktonic growth. After confirmatory dose-response assays, iodoquinol and miltefosine were selected as the two main leading repositionable compounds. Iodoquinol displayed potent in vitro inhibitory activity against planktonic C. auris but showed negligible inhibitory activity against biofilms; whereas miltefosine was able to inhibit the growth of C. auris under both planktonic and biofilm-growing conditions. Subsequent experiments confirmed their activity against nine other strains C. auris clinical isolates, irrespective of their susceptibility profiles against conventional antifungals. We extended our studies further to seven different species of Candida, also with similar findings. Conclusion. Both drugs possess broad spectrum of activity against Candida spp., including multiple strains of the emergent C. auris, and may constitute promising repositionable options for the development of novel therapeutics for the treatment of candidiasis.

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Section: Discussionmentioning

confidence: 99%

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

Wall

Herrera

Lopez-Ribot

2019

JoF

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“…S1 and S2 in the supplemental material). These data are in agreement with disturbances in the plasma membrane observed after MFS treatment in other fungi, such as S. brasiliensis, Paracoccidioides spp., Coccidioides immitis, and H. capsulatum (5,7,10).…”

Section: Discussionmentioning

confidence: 99%

“…On human fungal pathogens, the only alterations described after MFS treatment were abnormalities in plasma membrane morphology in Sporothrix brasiliensis (5) and Paracoccidioides spp. (10) and increased plasma membrane permeability and a reduction in total ergosterol in C. posadasii and H. capsulatum (7). For Cryptococcus neoformans yeasts, MFS inhibited, in vitro, both the fungal growth and the activity of phospholipase B1, an important virulence factor for Cryptococcus pathogenesis (4).…”

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confidence: 99%

Miltefosine Has a Postantifungal Effect and Induces Apoptosis in Cryptococcus Yeasts

Spadari

Vila

Rozental

et al. 2018

Antimicrob Agents Chemother

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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.

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“…The CFU were counted. The effect was considered fungicidal only when the CFU reduction was 3 log 10 (≥99.9%); otherwise, it was considered fungistatic [23].…”

Section: Methodsmentioning

confidence: 99%

Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

Rodrigues-Vendramini¹,

Faria²,

Arita³

et al. 2019

PLoS Negl Trop Dis

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Paracoccidioidomycosis (PCM) is a neglected disease present in Latin America with difficulty in treatment and occurrence of serious sequelae. Thus, the development of alternative therapies is imperative. In the current work, two oxadiazole compounds (LMM5 and LMM11) presented fungicidal activity against Paracoccidioides spp. The minimum inhibitory and fungicidal concentration values ranged from 1 to 32 μg/mL, and a synergic effect was observed for both compounds when combined with Amphotericin B. LMM5 and LMM11 were able to reduce CFU counts (�2 log 10) on the 5 th and 7 th days of time-kill curve, respectively. The fungicide effect was confirmed by fluorescence microscopy (FUN-1/FUN-2). The hippocratic screening and biochemical analysis were performed in Balb/c male mice that received a high dose of each compound, and the compounds showed no in vivo toxicity. The treatment of experimental PCM with the new oxadiazoles led to significant reduction in CFU (�1 log 10). Histopathological analysis of the groups treated exhibited control of inflammation, as well as preserved lung areas. These findings suggest that LMM5 and LMM11 are promising hits structures, opening the door for implementing new PCM therapies.

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

Cited by 30 publications

References 36 publications

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

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

Miltefosine Has a Postantifungal Effect and Induces Apoptosis in Cryptococcus Yeasts

Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

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