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Time-course proteome analysis reveals the dynamic response of Cryptococcus gattii cells to fluconazole.

Chong HS, Campbell L, Padula MP, Hill C, Harry E, Li SS, Wilkins MR, Herbert B, Carter D - PLoS ONE (2012)

Bottom Line: During FLC treatment, an increase in stress response, ATP synthesis and mitochondrial respiratory chain proteins, and a decrease in most ribosomal proteins was observed, suggesting that ATP-dependent efflux pumps had been initiated for survival and that the maintenance of ribosome synthesis was differentially expressed.An integrative network analysis revealed co-ordinated processes involved in drug response, and highlighted hubs in the network representing essential proteins that are required for cell viability.This work demonstrates the dynamic cellular response of a typical susceptible isolate of C. gattii to FLC, and identified a number of proteins and pathways that could be targeted to augment the activity of FLC.

View Article: PubMed Central - PubMed

Affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia.

ABSTRACT
Cryptococcus gattii is an encapsulated fungus capable of causing fatal disease in immunocompetent humans and animals. As current antifungal therapies are few and limited in efficacy, and resistance is an emerging issue, the development of new treatment strategies is urgently required. The current study undertook a time-course analysis of the proteome of C. gattii during treatment with fluconazole (FLC), which is used widely in prophylactic and maintenance therapies. The aims were to analyze the overall cellular response to FLC, and to find fungal proteins involved in this response that might be useful targets in therapies that augment the antifungal activity of FLC. During FLC treatment, an increase in stress response, ATP synthesis and mitochondrial respiratory chain proteins, and a decrease in most ribosomal proteins was observed, suggesting that ATP-dependent efflux pumps had been initiated for survival and that the maintenance of ribosome synthesis was differentially expressed. Two proteins involved in fungal specific pathways were responsive to FLC. An integrative network analysis revealed co-ordinated processes involved in drug response, and highlighted hubs in the network representing essential proteins that are required for cell viability. This work demonstrates the dynamic cellular response of a typical susceptible isolate of C. gattii to FLC, and identified a number of proteins and pathways that could be targeted to augment the activity of FLC.

Show MeSH
Categories of proteins that were present only in the FLC-treated or in the untreated samples.Proteins involved in energy production, protein metabolism and ribosomal protein synthesis were substantially reduced in the FLC-treated cells, while the number of unknown proteins increased in the FLC-treated cells.
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pone-0042835-g003: Categories of proteins that were present only in the FLC-treated or in the untreated samples.Proteins involved in energy production, protein metabolism and ribosomal protein synthesis were substantially reduced in the FLC-treated cells, while the number of unknown proteins increased in the FLC-treated cells.

Mentions: In the untreated samples, a total of 195 proteins were identified, while 152 proteins were identified across all of the FLC-treated samples. When all of the proteins identified were compared, 12 were found only in the FLC-treated samples. The majority of proteins found only in the untreated samples had functions involving protein or amino acid metabolism, ribosomal biosynthesis or energy metabolism including respiration and glycolysis. In contrast, most of the proteins found only in the FLC-treated samples were uncharacterized proteins without known functions, or were involved in protein and sugar metabolism (Figure 3; Table S1).


Time-course proteome analysis reveals the dynamic response of Cryptococcus gattii cells to fluconazole.

Chong HS, Campbell L, Padula MP, Hill C, Harry E, Li SS, Wilkins MR, Herbert B, Carter D - PLoS ONE (2012)

Categories of proteins that were present only in the FLC-treated or in the untreated samples.Proteins involved in energy production, protein metabolism and ribosomal protein synthesis were substantially reduced in the FLC-treated cells, while the number of unknown proteins increased in the FLC-treated cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412811&req=5

pone-0042835-g003: Categories of proteins that were present only in the FLC-treated or in the untreated samples.Proteins involved in energy production, protein metabolism and ribosomal protein synthesis were substantially reduced in the FLC-treated cells, while the number of unknown proteins increased in the FLC-treated cells.
Mentions: In the untreated samples, a total of 195 proteins were identified, while 152 proteins were identified across all of the FLC-treated samples. When all of the proteins identified were compared, 12 were found only in the FLC-treated samples. The majority of proteins found only in the untreated samples had functions involving protein or amino acid metabolism, ribosomal biosynthesis or energy metabolism including respiration and glycolysis. In contrast, most of the proteins found only in the FLC-treated samples were uncharacterized proteins without known functions, or were involved in protein and sugar metabolism (Figure 3; Table S1).

Bottom Line: During FLC treatment, an increase in stress response, ATP synthesis and mitochondrial respiratory chain proteins, and a decrease in most ribosomal proteins was observed, suggesting that ATP-dependent efflux pumps had been initiated for survival and that the maintenance of ribosome synthesis was differentially expressed.An integrative network analysis revealed co-ordinated processes involved in drug response, and highlighted hubs in the network representing essential proteins that are required for cell viability.This work demonstrates the dynamic cellular response of a typical susceptible isolate of C. gattii to FLC, and identified a number of proteins and pathways that could be targeted to augment the activity of FLC.

View Article: PubMed Central - PubMed

Affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia.

ABSTRACT
Cryptococcus gattii is an encapsulated fungus capable of causing fatal disease in immunocompetent humans and animals. As current antifungal therapies are few and limited in efficacy, and resistance is an emerging issue, the development of new treatment strategies is urgently required. The current study undertook a time-course analysis of the proteome of C. gattii during treatment with fluconazole (FLC), which is used widely in prophylactic and maintenance therapies. The aims were to analyze the overall cellular response to FLC, and to find fungal proteins involved in this response that might be useful targets in therapies that augment the antifungal activity of FLC. During FLC treatment, an increase in stress response, ATP synthesis and mitochondrial respiratory chain proteins, and a decrease in most ribosomal proteins was observed, suggesting that ATP-dependent efflux pumps had been initiated for survival and that the maintenance of ribosome synthesis was differentially expressed. Two proteins involved in fungal specific pathways were responsive to FLC. An integrative network analysis revealed co-ordinated processes involved in drug response, and highlighted hubs in the network representing essential proteins that are required for cell viability. This work demonstrates the dynamic cellular response of a typical susceptible isolate of C. gattii to FLC, and identified a number of proteins and pathways that could be targeted to augment the activity of FLC.

Show MeSH