Cargando…

De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans

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 di...

Descripción completa

Detalles Bibliográficos
Autores principales: 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, Ulrike, Kobe, Bostjan, Fraser, James A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469657/
https://www.ncbi.nlm.nih.gov/pubmed/23071437
http://dx.doi.org/10.1371/journal.ppat.1002957
_version_ 1782246121689579520
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, Ulrike
Kobe, Bostjan
Fraser, James A.
author_facet 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, Ulrike
Kobe, Bostjan
Fraser, James A.
author_sort Morrow, Carl A.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3469657
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-34696572012-10-15 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, Ulrike Kobe, Bostjan Fraser, James A. PLoS Pathog Research Article 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. Public Library of Science 2012-10-11 /pmc/articles/PMC3469657/ /pubmed/23071437 http://dx.doi.org/10.1371/journal.ppat.1002957 Text en © 2012 Morrow et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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, Ulrike
Kobe, Bostjan
Fraser, James A.
De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans
title De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans
title_full De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans
title_fullStr De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans
title_full_unstemmed De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans
title_short De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans
title_sort de novo gtp biosynthesis is critical for virulence of the fungal pathogen cryptococcus neoformans
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469657/
https://www.ncbi.nlm.nih.gov/pubmed/23071437
http://dx.doi.org/10.1371/journal.ppat.1002957
work_keys_str_mv AT morrowcarla denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT valkoveugene denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT stampanna denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT chowevewl denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT leeirussel denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT wronskiania denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT williamssimonj denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT hilljustinem denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT djordjevicjuliannet denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT kapplerulrike denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT kobebostjan denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans
AT fraserjamesa denovogtpbiosynthesisiscriticalforvirulenceofthefungalpathogencryptococcusneoformans