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Anti-Cryptococcal activity of a furanone derivative-antibiofilm and opsonophagocytic potential
S S Rathore1, T Raman2, C Lalitha1
1Actinomycetes Bioprospecting Lab, Centre for Research in Infectious Diseases (CRID), School of Chemical and Biotechnology, SASTRA University, Tirumalaisamudram, 613401 Thanjavur, Tamilnadu, India.
Abstract:
Cryptococcus neoformans, an encapsulated fungal pathogen is evolving as a major threat to immune-compromised patients and rarely to healthy individuals also. The cell wall bound capsular polysaccharide, melanin pigment and biofilm formation are major virulence factors that are known to contribute to cryptococcal meningitis. In the present study, a furanone derivative, (E)-5-benzylidenedihydrofuran-2(3H)-one (compound-6) was evaluated against biofilm of seven different strains of C. neoformans in melanized and non-melanized condition. In addition, the efficacy of compound-6 in activation of TLR-2, opsonophagocytosis, and modulation of cytokine expression during phagocytosis were studied. During the biofilm study, we found that moderate capsule size favored biofilm formation. Interestingly, the minimum biofilm eradication concentration (MBEC0.5) of melanized biofilm was found to be achieved at 1- to 1.7-fold higher MBEC0.5 of non-melanized cells. The maximum eradication of 77% and 69% of non-melanized and melanized biofilm were observed. The capsule size was reduced to half of its size with marked changes in morphology. Furthermore, expression of TLR2, iNOS and pro-inflammatory cytokines such as TNF-α, IL-12, and IFN-γ were also facilitated by compound-6. The correlation analysis showed a positive correlation between phagocytosis and the expression of TLR-2, iNOS, IL-6, IL-12. Collectively, the significant effect of compound-6, anti-melanization activity, antibiofilmand effective immunomodulant could be an interesting dual strategy drug agonist against cryptococcal meningitis.
Insights
A novel compound, (E)-5-benzylidenedihydrofuran-2(3H)-one (compound-6), effectively targets Cryptococcus neoformans biofilms and melanization. It also enhances immune responses, showing potential as a dual-action drug against cryptococcal meningitis.
Area of Science:
- Mycology
- Immunology
- Pharmacology
Background:
- Cryptococcus neoformans is a significant fungal pathogen, particularly threatening immunocompromised individuals.
- Key virulence factors include capsular polysaccharide, melanin, and biofilm formation, contributing to cryptococcal meningitis.
- Melanized biofilms present a greater challenge for eradication.
Purpose of the Study:
- To evaluate the efficacy of a furanone derivative, (E)-5-benzylidenedihydrofuran-2(3H)-one (compound-6), against Cryptococcus neoformans biofilms.
- To assess compound-6's impact on melanization, capsule size, and immune system activation.
- To explore compound-6 as a potential therapeutic agent for cryptococcal meningitis.
Main Methods:
- Testing compound-6 against melanized and non-melanized C. neoformans biofilms from seven strains.
- Assessing compound-6's effects on Toll-like receptor 2 (TLR-2) activation and opsonophagocytosis.
- Analyzing the modulation of cytokine expression (TNF-α, IL-12, IFN-γ) during phagocytosis.
Main Results:
- Compound-6 demonstrated significant antibiofilm activity, eradicating up to 77% of non-melanized and 69% of melanized biofilms.
- Melanized biofilms required higher concentrations for eradication compared to non-melanized biofilms.
- Compound-6 reduced capsule size, facilitated TLR-2 expression, iNOS, and pro-inflammatory cytokines, positively correlating with phagocytosis.
Conclusions:
- Compound-6 exhibits potent anti-melanization and antibiofilm properties against C. neoformans.
- The compound acts as an effective immunomodulant, enhancing phagocytosis and cytokine production.
- Compound-6 presents a promising dual-strategy therapeutic candidate for treating cryptococcal meningitis.
