Organoselenium Has a Potent Fungicidal Effect on Cryptococcus neoformans and Inhibits the Virulence Factors

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De Jesus, Daniel Felipe Freitas ; De Freitas, Aline Luiza Duarte ; De Oliveira, Isadora Maria ; De Almeida, Larissa Costa ; Bastos, Rafael Wesley ; Spadari, Cristina de Castro ; Melo, Analy Sales de Azevedo ; Santos, Daniel de Assis ; Costa-Lotufo, Leticia Veras ; Reis, Flavia C. G. ; Rodrigues, Marcio L. ; Stefani, Helio Alexandre ; Ishida, Kelly

• Document type: Journal article
• Source: Antimicrobial Agents and Chemotherapy; v. 67, n. 3, p. 16-pg., 2023-02-23.

Abstract

Cryptococcosis therapy is often limited by toxicity problems, antifungal tolerance, and high costs. Studies approaching chalcogen compounds, especially those containing selenium, have shown promising antifungal activity against pathogenic species. Cryptococcosis therapy is often limited by toxicity problems, antifungal tolerance, and high costs. Studies approaching chalcogen compounds, especially those containing selenium, have shown promising antifungal activity against pathogenic species. This work aimed to evaluate the in vitro and in vivo antifungal potential of organoselenium compounds against Cryptococcus neoformans. The lead compound LQA_78 had an inhibitory effect on C. neoformans planktonic cells and dispersed cells from mature biofilms at similar concentrations. The fungal growth inhibition led to an increase in budding cells arrested in the G(2)/M phase, but the compound did not significantly affect structural cell wall components or chitinase activity, an enzyme that regulates the dynamics of the cell wall. The compound also inhibited titan cell (Tc) and enlarged capsule yeast (NcC) growth and reduced the body diameter and capsule thickness associated with increased capsular permeability of both virulent morphotypes. LQA_78 also reduced fungal melanization through laccase activity inhibition. The fungicidal activity was observed at higher concentrations (16 to 64 mu g/mL) and may be associated with augmented plasma membrane permeability, ROS production, and loss of mitochondrial membrane potential. While LQA_78 is a nonhemolytic compound, its cytotoxic effects were cell type dependent, exhibiting no toxicity on Galleria mellonella larvae at a dose <= 46.5 mg/kg. LQA_78 treatment of larvae infected with C. neoformans effectively reduced the fungal burden and inhibited virulent morphotype formation. To conclude, LQA_78 displays fungicidal action and inhibits virulence factors of C. neoformans. Our results highlight the potential use of LQA_78 as a lead molecule for developing novel pharmaceuticals for treating cryptococcosis. (AU)

• FAPESP's process: 16/04289-3 - Synthesis of calcogeno amino acids derivatives and 4-calcogeno quinolines via multicomponent reactions
• Grantee: Isadora Maria de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• 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
• FAPESP's process: 21/01279-5 - Investigation of new targets and antifungal molecules on Candida spp. and Cryptococcus spp.
• Grantee: Kelly Ishida
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/12149-2 - Nanoparticles as carriers of miltefosine for treatment of cryptococcal meningitis.
• Grantee: Cristina de Castro Spadari
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/00295-4 - Functionalization of D-glucal and analogs via carbonylative coupling reactions
• Grantee: Helio Alexandre Stefani
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
• Grantee: Leticia Veras Costa Lotufo
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants