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Novel Antifungal Activity for the Lectin Scytovirin: Inhibition of Cryptococcus neoformans and Cryptococcus gattii.

ABSTRACT: Pathogenic cryptococci are encapsulated yeast that can cause severe meningoencephalitis. Existing therapeutic options are dated and there is a growing need for new alternative antifungal agents for these fungi. Here we report novel inhibition of pathogenic cryptococci by the antimicrobial lectin Scytovirin. Inhibition was most potent against Cryptococcus neoformans var neoformans and C. gattii, with MFC values of 500 nM. Scytovirin binding was localized to the cell wall and shown to affect capsule size and release. No effect was observed on melanization or with cells grown in the presence the cell wall stressor Congo red. Synergy with existing antifungals was indicated, most strongly for amphotericin B. Overall, Scytovirin serves as a much needed new avenue for anticryptococcal development.

SUBMITTER: Jones TH

PROVIDER: S-EPMC5422485 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Novel Antifungal Activity for the Lectin Scytovirin: Inhibition of Cryptococcus neoformans and Cryptococcus gattii.

Jones Tyler H TH McClelland Erin E EE McFeeters Hana H McFeeters Robert L RL

Frontiers in microbiology 20170509

Pathogenic cryptococci are encapsulated yeast that can cause severe meningoencephalitis. Existing therapeutic options are dated and there is a growing need for new alternative antifungal agents for these fungi. Here we report novel inhibition of pathogenic cryptococci by the antimicrobial lectin Scytovirin. Inhibition was most potent against Cryptococcus neoformans var neoformans and C. gattii, with MFC values of 500 nM. Scytovirin binding was localized to the cell wall and ...[more]

PMID: 28536555

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Project description:BackgroundCryptoccocal 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.MethodsLiriodenine 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.ResultsLiriodenine 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.ConclusionThe 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.

Dataset Information

Novel Antifungal Activity for the Lectin Scytovirin: Inhibition of Cryptococcus neoformans and Cryptococcus gattii.

Publications

Novel Antifungal Activity for the Lectin Scytovirin: Inhibition of <i>Cryptococcus neoformans</i> and <i>Cryptococcus gattii</i>.

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