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Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents.

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.

SUBMITTER: Pereira de Sa N

PROVIDER: S-EPMC8497620 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents.

Pereira de Sa Nivea N Taouil Adam A Kim Jinwoo J Clement Timothy T Hoffmann Reece M RM Burke John E JE Rizzo Robert C RC Ojima Iwao I Del Poeta Maurizio M Airola Michael V MV

Nature communications 20211007 1

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 ...[more]

PMID: 34620873

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Project description:Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningitis in >152,000 immunocompromised individuals annually, leading to 112,000 yearly deaths. The four classes of existing antifungal agents target plasma membrane sterols (ergosterol), nucleic acid synthesis, and cell wall synthesis. Existing drugs are not highly effective against Cryptococcus, and antifungal drug resistance is an increasing problem. A novel antimicrobial compound, a eumelanin-inspired indoylenepheyleneethynylene, EIPE-1, was synthesized and has antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MSRA), but not towards Gram-negative organisms. Based on EIPE-1's antibacterial activity, we hypothesized that EIPE-1 could have antifungal activity. For these studies, we tested EIPE-1 against C. neoformans strain H99 and 6 additional cryptococcal clinical isolates. We examined antifungal activity, cytotoxicity, effects on fungal gene expression, and mechanism of action of EIPE-1. Results showed that EIPE-1 has fungicidal effects on seven cryptococcal strains with MICs ranging from 1.56 to 3.125 μg/mL depending on the strain, and it is non-toxic to mammalian cells. We conducted scanning and transmission electron microscopy on the exposed cells to examine structural changes to the organism following EIPE-1 treatment. Cells exposed displayed structural changes to their cell wall and membranes, with internal contents leaking out of the cells. To understand the effect of EIPE-1 on fungal gene expression, RNA sequencing was conducted. Results showed that EIPE-1 affects several processes involved stress response, ergosterol biosynthesis, capsule biosynthesis, and cell wall attachment and remodeling. Therefore, our studies demonstrate that EIPE-1 has antifungal activity against C. neoformans, which affects both cellular structure and gene expression of multiple fungal pathways involved in cell membrane stability and viability.

Dataset Information

Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents.

Publications

Structure and inhibition of Cryptococcus neoformans sterylglucosidase to develop antifungal agents.

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