De novo GTP biosynthesis is critical for virulence of the fungal pathogen cryptococcus neoformans

Morrow, Carl A., Valkov, Eugene, Stamp, Anna, Chow, Eve W. L., Lee, I. Russel, Wronski, Ania, Williams, Simon J., Hill, Justine M., Djordjevic, Julianne T., Kappler, Ulrke, Kobe, Bostjan and Fraser, James A. (2012) De novo GTP biosynthesis is critical for virulence of the fungal pathogen cryptococcus neoformans. PLoS Pathogens, 8 10: . doi:10.1371/journal.ppat.1002957


Author Morrow, Carl A.
Valkov, Eugene
Stamp, Anna
Chow, Eve W. L.
Lee, I. Russel
Wronski, Ania
Williams, Simon J.
Hill, Justine M.
Djordjevic, Julianne T.
Kappler, Ulrke
Kobe, Bostjan
Fraser, James A.
Title De novo GTP biosynthesis is critical for virulence of the fungal pathogen cryptococcus neoformans
Formatted title
De novo GTP biosynthesis is critical for virulence of the fungal pathogen cryptococcus neoformans
Journal name PLoS Pathogens   Check publisher's open access policy
ISSN 1553-7374
1553-7366
Publication date 2012-10-11
Sub-type Article (original research)
DOI 10.1371/journal.ppat.1002957
Open Access Status DOI
Volume 8
Issue 10
Total pages 17
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2013
Language eng
Formatted 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.
Keyword Inosine 5'-monophosphate dehydrogenase
Essential gene identification
Antifungal drug discovery
IMP dehydrogenase
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article #e1002957

 
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Created: Fri, 19 Oct 2012, 09:42:17 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences