ArticlePLoS pathogens2012
De novo GTP biosynthesis is critical for virulence of the fungal pathogen Cryptococcus neoformans.
Article in PLoS pathogens, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 63 citations in OpenAlex.
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- Compartmentalization and regulation of GTP in control of cellular phenotypes.Trends in molecular medicine · 2022Review
- De novo purine nucleotide biosynthesis mediated by MoAde4 is required for conidiation, host colonization and pathogenicity in Magnaporthe oryzae.Applied microbiology and biotechnology · 2022Article
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- In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors.Nature communications · 2020Article
- Targeting Unconventional Pathways in Pursuit of Novel Antifungals.Frontiers in molecular biosciences · 2020Review
- Quantitation of Purines from Pigeon Guano and Implications for Cryptococcus neoformans Survival During Infection.Mycopathologia · 2019Article
- MoImd4 mediates crosstalk between MoPdeH-cAMP signalling and purine metabolism to govern growth and pathogenicity in Magnaporthe oryzae.Molecular plant pathology · 2019Article
- Transcriptome-wide survey of gene expression changes and alternative splicing in Trichophyton rubrum in response to undecanoic acid.Scientific reports · 2018Article
- A Tet-Off gene expression system for validation of antifungal drug targets in a murine invasive pulmonary aspergillosis model.Scientific reports · 2018Article
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- A novel benzo-heterocyclic amine derivative N30 inhibits influenza virus replication by depression of Inosine-5'-Monophospate Dehydrogenase activity.Virology journal · 2017Article
- GMP Synthase Is Required for Virulence Factor Production and Infection byThe Journal of biological chemistry · 2017Article
- The Atypical Guanylate Kinase MoGuk2 Plays Important Roles in Asexual/Sexual Development, Conidial Septation, and Pathogenicity in the Rice Blast Fungus.Frontiers in microbiology · 2017Article
- Identification of factors involved in dimorphism and pathogenicity of Zymoseptoria tritici.PloS one · 2017Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We have investigated the potential of the GTP synthesis pathways as chemotherapeutic targets in the human pathogen Cryptococcus neoformans, a common cause of fatal fungal meningoencephalitis. We find that de novo GTP biosynthesis, but not the alternate salvage pathway, is critical to cryptococcal dissemination and survival in vivo. Loss of inosine monophosphate dehydrogenase (IMPDH) in the de novo pathway results in slow growth and virulence factor defects, while loss of the cognate phosphoribosyltransferase in the salvage pathway yielded no phenotypes. Further, the Cryptococcus species complex displays variable sensitivity to the IMPDH inhibitor mycophenolic acid, and we uncover a rare drug-resistant subtype of C. gattii that suggests an adaptive response to microbial IMPDH inhibitors in its environmental niche. We report the structural and functional characterization of IMPDH from Cryptococcus, revealing insights into the basis for drug resistance and suggesting strategies for the development of fungal-specific inhibitors. The crystal structure reveals the position of the IMPDH moveable flap and catalytic arginine in the open conformation for the first time, plus unique, exploitable differences in the highly conserved active site. Treatment with mycophenolic acid led to significantly increased survival times in a nematode model, validating de novo GTP biosynthesis as an antifungal target in Cryptococcus.
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Registered trials
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