Antifungal activity of liriodenine on clinical strains of Cryptococcus neoformans and Cryptococcus gattii species complexes

• Published in: Journal of Venomous Animals and Toxins including Tropical Diseases
• Main Authors: Adriele Dandara Levorato-Vinche, Marcia de Souza Carvalho Melhem, Lucas Xavier Bonfietti, Iván de-la-Cruz-Chacón, Carmen Sílvia Fernandes Boaro, Alexandre Todorovic Fabro, Gisela Ferreira, Julhiany de Fátima da Silva, Daniela Carvalho dos Santos, Beatriz Aparecida Soares Pereira, Camila Marçon, Lariza Maza, Lídia Raquel de Carvalho, Rinaldo Poncio Mendes
• Format: Article in Journal/Newspaper
• Language: English
• Published: SciELO 2022
• Subjects: Liriodenine; Yeast; Fungi; Fungal cell ultrastructure; Cryptococcus spp; Time-kill methodology; Arctic medicine. Tropical medicine; RC955-962; Toxicology. Poisons; RA1190-1270; Zoology; QL1-991; Arctic
• Online Access: https://doi.org/10.1590/1678-9199-jvatitd-2022-0006; https://doaj.org/article/70d041b710624a088041e1df9368e715

Abstract Background: Cryptoccocal meningitis continues to present high incidence among AIDS patients. The treatment of choice is the synergistic combination of flucytosine (5-FC) with amphotericin B deoxycholate (AmBd) or its lipid formulations. However, 5-FC is unavailable in many countries and AmB demands hospitalization. The combination of AmB with the fungistatic fluconazole (FLC) or the use of high FLC daily doses alone became the choice. Nonetheless, sterilization of cerebrospinal fluid is delayed with FLC monotherapy, mainly with high fungal burden. These findings suggest the search for new antifungal compounds, such as liriodenine. Methods: Liriodenine antifungal activity was evaluated by three procedures: determining the minimum inhibitory concentration (MIC) on 30 strains of the Cryptococcus neoformans (C. neoformans) complex and 30 of the Cryptococcus gattii (C. gattii) complex, using EUCAST methodology and amphotericin B deoxycholate as control; performing the time-kill methodology in two strains of the C. neoformans complex and one of the C. gattii complex; and injury to cryptococcal cells, evaluated by transmission electron microscopy (TEM). Liriodenine absorption and safety at 0.75 and 1.50 mg.kg-1 doses were evaluated in BALB/c mice. Results: Liriodenine MICs ranged from 3.9 to 62.5 μg.mL-1 for both species complexes, with no differences between them. Time-kill methodology confirmed its concentration-dependent fungicidal effect, killing all the strains below the limit of detection (33 CFU.mL-1) at the highest liriodenine concentration (32-fold MIC), with predominant activity during the first 48 hours. Liriodenine induced severe Cryptococcus alterations - cytoplasm with intense rarefaction and/or degradation, injury of organelles, and presence of vacuoles. Liriodenine was better absorbed at lower doses, with no histopathological alterations on the digestive tract. Conclusion: The fungicidal activity confirmed by time-kill methodology, the intense Cryptococcus injury observed by TEM, the absorption ...