Abstract
Cryptococcus gattii, an encapsulated yeast with a normally saprotrophic
lifestyle, can cause severe disease in immunocompetent people and
animals that may be fatal if not treated. As the antifungal therapies
used currently are either toxic to the host or limited in efficacy, and
resistance is an emerging issue, the development of new treatment
strategies is urgently required. However, this is problematic as there
are few fungal pathways that are sufficiently conserved among fungi to
allow broad-spectrum coverage, yet divergent enough from animals to
prevent undesirable side effects. A promising alternative approach to
developing new drugs is to develop therapies that work in synergy with
existing drugs by targeting cellular pathways that enhance drug action
or prevent resistance. The current study analysed the proteome of a
typically susceptible strain of C. gattii during treatment with fluconazole
(FLC), which is used 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 FLC activity. Three time points were
chosen for protein extraction: 3 h, when there was little difference in
growth in the treated and untreated cells; 4 h, when growth in the
presence of FLC had started to slow; and 6 h, when there was a clear
difference between treated and untreated cultures. During the course of
FLC treatment there was an increase in stress response, ATP synthesis
and mitochondrial respiratory chain proteins, and a decrease in most
ribosomal proteins. Two proteins involved in pathways specific to fungi
that might be less likely to incur side effects if targeted in antifungal
therapies were responsive to FLC. Analysis of how the differentially
expressed proteins and their interacting partners changed over time
using the Saccharomyces cereviseae inteactome database revealed
coordinated regulation of mitochondrial ATP synthase complex
proteins. This indicated that energy production was important for
surviving FLC, possibly through the induction of ATP-dependent efflux
pumps. The interactome further revealed the dynamic nature of the
drug response, and highlighted hub proteins likely to be essential for
cell viability. Overall, this study showed how C. gattii cells respond to
FLC in a dynamic way, and revealed a number of proteins and
pathways that might be useful for enhancing FLC activity.
lifestyle, can cause severe disease in immunocompetent people and
animals that may be fatal if not treated. As the antifungal therapies
used currently are either toxic to the host or limited in efficacy, and
resistance is an emerging issue, the development of new treatment
strategies is urgently required. However, this is problematic as there
are few fungal pathways that are sufficiently conserved among fungi to
allow broad-spectrum coverage, yet divergent enough from animals to
prevent undesirable side effects. A promising alternative approach to
developing new drugs is to develop therapies that work in synergy with
existing drugs by targeting cellular pathways that enhance drug action
or prevent resistance. The current study analysed the proteome of a
typically susceptible strain of C. gattii during treatment with fluconazole
(FLC), which is used 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 FLC activity. Three time points were
chosen for protein extraction: 3 h, when there was little difference in
growth in the treated and untreated cells; 4 h, when growth in the
presence of FLC had started to slow; and 6 h, when there was a clear
difference between treated and untreated cultures. During the course of
FLC treatment there was an increase in stress response, ATP synthesis
and mitochondrial respiratory chain proteins, and a decrease in most
ribosomal proteins. Two proteins involved in pathways specific to fungi
that might be less likely to incur side effects if targeted in antifungal
therapies were responsive to FLC. Analysis of how the differentially
expressed proteins and their interacting partners changed over time
using the Saccharomyces cereviseae inteactome database revealed
coordinated regulation of mitochondrial ATP synthase complex
proteins. This indicated that energy production was important for
surviving FLC, possibly through the induction of ATP-dependent efflux
pumps. The interactome further revealed the dynamic nature of the
drug response, and highlighted hub proteins likely to be essential for
cell viability. Overall, this study showed how C. gattii cells respond to
FLC in a dynamic way, and revealed a number of proteins and
pathways that might be useful for enhancing FLC activity.
| Original language | English |
|---|---|
| Article number | P064 |
| Pages (from-to) | 115-116 |
| Number of pages | 2 |
| Journal | Mycoses |
| Volume | 55 |
| Issue number | s4 |
| Publication status | Published - Jun 2012 |
| Event | 18th Congress of the International Society for Human and Animal Mycology - Berlin, Germany Duration: 11 Jun 2012 → 15 Jun 2012 |