Exploration of Antifungal and Immunomodulatory Potentials of a Furanone Derivative to Rescue Disseminated Cryptococosis in Mice

Abstract

Cryptococcus neoformans infection is quite complex with both host-pathogen interaction and host immune profile determining disease progress and therapeutic outcome. Hence in the present study, the potential utility of (E)-5-benzylidenedihydrofuran-2(3 H)-one (compound-6) was explored as an effective anticryptococcal compound with immunomodulatory potential. The efficacy of compound-6 in pulmonary cryptococosis model using H99 strain was investigated. The effective dose was found to provide 100% survival, with a significant reduction of yeast burden in lungs and brain. The biodistribution analysis provided evidence for the presence of higher concentration of compound-6 in major organs including lungs and brain. In addition, compound-6 treated mice had significantly higher expression of IL-6, IL-4 and IFN-γ in lung and brain. Similarly, elevated expression of TNF-α, IL-β1 and IL-12 were observed in lungs, suggesting the protective host response against C. neoformans. The reduction and clearance of fungal load in systemic organs and mouse survival are notable results to confirm the ability of compound-6 to treat cryptococcosis. In conclusion, the low molecular weight (174 Da), lipophilicity, its ability to cross blood brain barrier, and facilitating modulation of cytokine expression are the added advantages of compound-6 to combat against disseminated cryptococosis.

Autoimmunity and clinical pathology amelioration in SLE by Dexamethasone primed Mesenchymal Stem Cell derived conditioned media

“…Pneumocytes, alveolar lumina, and blood vessels were also normal. Few alveolar macrophages, which are normally present in the alveolar wall, have been observed earlier too (Rathore et al, 2017). Bronchial walls and epithelial cells were normal.…”

Elucidation of furanone as ergosterol pathway inhibitor in Cryptococcus neoformans

“…In our previous study, Compound 6 has proved to have an immunomodulatory and antifungal activity against C. neoformans, A. fumigatus and C. albicans. The therapeutic potency was displayed with 100% survival of mice in a disseminated cryptococcal infection mice model [22] [Rathore et al, 2017]. In addition, the acute toxicity study displayed the safety pro le and bioavailability of Compound 6 in major organs advocates the compound to further investigate the mode of action The present study aimed to determine the mode of action of compound 6 and other furanone derivatives against various target proteins of ergosterol biosynthetic pathway (Fig.…”

“…Furanone and its derivatives have immense and broad spectrum therapeutic potential that serves as an antibacterial, antibio lm, antiprotozoa, antiulcerative agent, analgesic, anticancer, antiin ammatory, and it also acts as vasorelaxant [20]. The antifungal potentials of furanone were rst explored by our team [22].…”