Adamantylidene-substituted alkylphosphocholine TCAN26 is more active against Sporothrix schenckii than miltefosine.

Luana Pereira Borba-Santos,Wanderley De Souza,Kelly Ishida,Sonia Rozental,Theodora Calogeropoulou

doi:10.1590/0074-02760160088

Abstract

Sporotrichosis is the most frequent subcutaneous mycosis in the world and its increasing incidence has led to the search for new therapeutic options for its treatment. In this study, we demonstrated that three structural analogues of miltefosine (TCAN26, TC19, and TC70) showed inhibitory activity against Sporothrix schenckii sensu stricto and that TCAN26 was more active in vitro than miltefosine against several isolates. Scanning electron microscopy showed that S. schenckii exposure to TCAN26 resulted in cells that were slightly more elongated than untreated cells. Transmission electron microscopy showed that TCAN26 treatment induced loss of the regular cytoplasmic electron-density and altered the cell envelope (disruption of the cell membrane and cell wall, and increased cell wall thickness). Additionally, TCAN26 concentrations required to kill S. schenckii cells were lower than concentrations that were cytotoxic in mammalian cells, and TCAN26 was more selective than miltefosine. Thus, the adamantylidene-substituted alkylphosphocholine TCAN26 is a promising molecule for the development of novel antifungal compounds, although further investigations are required to elucidate the mode of action of TCAN26 in S. schenckii cells.

Highlights

Sporotrichosis has emerged as the most frequent subcutaneous mycosis in the world (Chakrabarti et al 2015), and has become a major public health problem in Brazil (Freitas et al 2014)
The isolates were cultivated in potato dextrose agar (PDA) medium at 35oC for seven days, to obtain the filamentous form, or in brain heart infusion (BHI; Difco, Detroit, USA) broth supplemented with 2% glucose at 36oC with orbital agitation (150 rpm) to obtain the yeast phase
Antifungal activity of compounds was evaluated according to minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs)

Summary

Introduction

Sporotrichosis has emerged as the most frequent subcutaneous mycosis in the world (Chakrabarti et al 2015), and has become a major public health problem in Brazil (Freitas et al 2014). Yeasts were treated with a sub-inhibitory concentration (1/4 MIC) of the most active miltefosine analogue, for 24 h at 35oC. To determine the selectivity of the most active miltefosine analogue toward S. schenckii, cytotoxicity assays were performed on mammalian cells [monkey epithelial cells from kidney (LLC-MK2)] and human erythrocytes, using concentrations of 1-100 μg/mL as described previously (Borba-Santos et al 2016), and the results were compared with those obtained for miltefosine.

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Conclusion