Robyn Rutgers ’24
Upon entering the lungs, the fungal pathogen Cryptococcus neoformans (CN) disseminates through the bloodstream and can cause life-threatening meningitis in immunocompromised patients. Currently, there are a number of major drawbacks in current antifungal agents such as high toxicity, limited availability, and a narrow spectrum of activity. Therefore, the development of new pharmacological agents is critical in combating fungal pathogens such as CN. In a recent study, researchers at Stony Brook University have identified a new approach in developing a new class of improved antifungal agents: investigating the role of sterylglucosidase 1 (Sg11).
Previous studies suggested that the genetic deletion of Sgl1 in CN stops the spread of the pathogen. Sgl1 is an enzyme that converts ergosterol 3-beta-D-glucoside, an immunomodulatory glycolipid, into ergosterol and glucose. Therefore, researchers were interested in the enzyme Sgl1 as a starting point for developing a new class of antifungal agents. The aim of this study was to determine the small-molecule inhibitors of Sgl1. Researchers employed a high-throughput screening (HTS) tiered approach to screen 50,000 compounds and identify potential competitive inhibitors of Sg11. The HTS campaign identified three compounds (Hit 1, Hit 9, and Hit 15) that potentially inhibited CN activity. Upon further experimentation, treatment of wild-type CN with 50µM of Hit 1, 9, or 15 resulted in a lack of CN growth, however, no treatment completely cleared the infection. Additionally, researchers found that Hit 1 decreased Sgl1 activity and may prevent the fungus from leaving the lung.
The results of this study provide evidence that the pharmacological inhibition properties of Sgl1 have the potential to treat fungal infections. However, further research is necessary to apply these findings by developing new antifungal agents. Because current antifungal agents are outdated and have significant drawbacks, the findings of this study provide important insight into the future development of antifungal agents that could prevent both primary and secondary infections. Future research into this topic may explore new derivatives of Sg11’s inhibitors to investigate whether complete clearance of infection can occur.
 N. Pereira de Sa, et al., Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents. Nature Communications 12, 1-12 (2021). doi: /10.1038/s41467-021-26163-5.