Dataset Information

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

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 after gavage administration, and the safety at the tested doses indicate that the liriodenine molecule is a promising drug lead for development of anticryptococcal agents.

SUBMITTER: Levorato-Vinche AD

PROVIDER: S-EPMC9469771 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Antifungal activity of liriodenine on clinical strains of <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i> species complexes.

Levorato-Vinche Adriele Dandara AD Melhem Marcia de Souza Carvalho MSC Bonfietti Lucas Xavier LX de-la-Cruz-Chacón Iván I Boaro Carmen Sílvia Fernandes CSF Fabro Alexandre Todorovic AT Ferreira Gisela G da Silva Julhiany de Fátima JF Dos Santos Daniela Carvalho DC Pereira Beatriz Aparecida Soares BAS Marçon Camila C Maza Lariza L de Carvalho Lídia Raquel LR Mendes Rinaldo Poncio RP

The journal of venomous animals and toxins including tropical diseases 20220905

<h4>Background</h4>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 d ...[more]

PMID: 36118844

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