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

Autor:	Levorato-Vinche AD; Department of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP), Botucatu, SP, Brazil., Melhem MSC; Mycology Unit, Adolfo Lutz Institute, Public Health Reference Laboratory, Secretariat of Health of the State of São Paulo, São Paulo, SP, Brazil.; Medical School, Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil., Bonfietti LX; Mycology Unit, Adolfo Lutz Institute, Public Health Reference Laboratory, Secretariat of Health of the State of São Paulo, São Paulo, SP, Brazil., de-la-Cruz-Chacón I; Instituto de Ciencias Biológicas, Universidad de Ciencias y Artes de Chiapas, Tuxtla Gutierrez, Chiapas, Mexico., Boaro CSF; Department of Biostatistics, Plant Biology, Parasitology and Zoology, Botucatu Biosciences Institute, São Paulo State University (UNESP), Botucatu, SP, Brazil., Fabro AT; Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil., Ferreira G; Department of Biostatistics, Plant Biology, Parasitology and Zoology, Botucatu Biosciences Institute, São Paulo State University (UNESP), Botucatu, SP, Brazil., da Silva JF; Department of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP), Botucatu, SP, Brazil., Dos Santos DC; Department of Structural and Functional Biology, Botucatu Biosciences Institute, São Paulo State University (UNESP), Botucatu, SP, Brazil., Pereira BAS; Department of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP), Botucatu, SP, Brazil., Marçon C; Department of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP), Botucatu, SP, Brazil., Maza L; Department of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP), Botucatu, SP, Brazil., de Carvalho LR; Department of Biostatistics, Plant Biology, Parasitology and Zoology, Botucatu Biosciences Institute, São Paulo State University (UNESP), Botucatu, SP, Brazil., Mendes RP; Department of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Botucatu Medical School (FMB), São Paulo State University (UNESP), Botucatu, SP, Brazil.
Jazyk:	angličtina
Zdroj:	The journal of venomous animals and toxins including tropical diseases [J Venom Anim Toxins Incl Trop Dis] 2022 Sep 05; Vol. 28, pp. e20220006. Date of Electronic Publication: 2022 Sep 05 (Print Publication: 2022).
DOI:	10.1590/1678-9199-JVATITD-2022-0006
Abstrakt:	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. Competing Interests: Competing interests: The authors declare that they have no competing interests.
Databáze:	MEDLINE
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