Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents

Date

2021

Authors

Pereira de Sa, Nivea
Taouil, Adam
Kim, Jinwoo
Clement, Timothy
Hoffmann, Reece M.
Burke, John E.
Rizzo, Robert C.
Ojima, Iwao
Del Poeta, Maurizio
Airola, Michael V.

Journal Title

Journal ISSN

Volume Title

Publisher

Nature Communications

Abstract

Pathogenic fungi exhibit a heavy burden on medical care and new therapies are needed. Here, we develop the fungal specific enzyme sterylglucosidase 1 (Sgl1) as a therapeutic target. Sgl1 converts the immunomodulatory glycolipid ergosterol 3β-D-glucoside to ergosterol and glucose. Previously, we found that genetic deletion of Sgl1 in the pathogenic fungus Cryptococcus neoformans (Cn) results in ergosterol 3β-D-glucoside accumulation, renders Cn non-pathogenic, and immunizes mice against secondary infections by wild-type Cn, even in condition of CD4+ T cell deficiency. Here, we disclose two distinct chemical classes that inhibit Sgl1 function in vitro and in Cn cells. Pharmacological inhibition of Sgl1 phenocopies a growth defect of the Cn Δsgl1 mutant and prevents dissemination of wild-type Cn to the brain in a mouse model of infection. Crystal structures of Sgl1 alone and with inhibitors explain Sgl1’s substrate specificity and enable the rational design of antifungal agents targeting Sgl1.

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Citation

Pereira de Sa, N., Taouil, A., Kim, J. et al. (2021). Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents. Nat Commun 12, 5885. https://doi.org/10.1038/s41467-021-26163-5