The dynamic response of Cryptococcus gattii cells to fluconazole: a time-course analysis of the proteome and interactome

H. Siong Chong, L. T. Campbell, M. P. Padula, E. Harry, C. Hill, S. Li, B. Herbert, M. R. Wilkins, D. A. Carter

    Research output: Contribution to journalMeeting 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.
    Original languageEnglish
    Article numberP064
    Pages (from-to)115-116
    Number of pages2
    Issue numbers4
    Publication statusPublished - Jun 2012
    Event18th Congress of the International Society for Human and Animal Mycology - Berlin, Germany
    Duration: 11 Jun 201215 Jun 2012


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