Analysis of the antifungal effect of synthetic compounds on Cryptococcus spp.

Author(s)

Aline Luiza Duarte de Freitas

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2019-12-02

Examining board members

Kelly Ishida; Sandro Rogerio de Almeida; Lucas Xavier Bonfietti; Benedito Correa

• Advisor: Kelly Ishida

Abstract

Cryptococcosis therapy is limited by toxicity problems, antifungal tolerance and high cost. Studies with organic chalcogen compounds, especially those containing selenium, have shown their activity against microorganisms, including fungi. Thus, the objective of this work was to evaluate the antifungal potential of synthetic chalcogen compounds in the control of Cryptococcus spp. using in vitro and in vivo models. After the screening of 141 compounds on Aspergillus fumigatus, Fusarium solani, Candida albicans and Cryptococcus neoformans for antifungal activity and red blood cell toxicity evaluation, the ALDF_078 compound was selected as leader molecule for anticryptococcal activity evaluation. This compound showed antifungal activity on C. neoformans H99 and C. gattii R265 and their fluconazole (FCZ) tolerant strains, and also on the clinical isolates of the two species (IC50: 1 8 μg/mL). The concentrations at 4X and 8X CI50 of ALDF_078 presented fungicidal effect on C. neoformans H99 after 8h and 4h of molecule exposure, respectively. Treatment of the yeasts with the compound caused a decrease in capsule thickness and cell volume of Cryptococcus spp., besides to increasing membrane permeability of FCZ tolerant C. neoformans H99 yeasts. The dispersion cells from non-adapted C. neoformans H99 mature biofilm were inhibited at similar concentrations that inhibited planktonic cells of the same strain; however, this molecule was unable to interfere with mature biofilm cells. Galleria mellonella invertebrate model experiments have shown that doses below 46.5 mg/kg of ALDF_078, although were not toxic in the tested model, were not effective in treating the infection with C. neoformans. Our data show that the compound ALDF_078 has fungicidal effect, low toxicity and morphophysiological effects on Cryptococcus spp. and highlighted the potential of this synthetic compound as a leader molecule in the development of a therapeutic option for cryptococcosis agents. (AU)

• FAPESP's process: 17/15226-5 - Analysis of the antifungal effect of synthetic compounds on Cryptococcus spp.
• Grantee: Aline Luiza Duarte de Freitas
• Support Opportunities: Scholarships in Brazil - Master