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The response of the yeast pathogen Candida albicans to antifungal agents

English title The response of the yeast pathogen Candida albicans to antifungal agents
Applicant Sanglard Dominique
Number 114131
Funding scheme Project funding
Research institution Institut de Microbiologie - CHUV Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Medical Microbiology
Start/End 01.10.2006 - 28.02.2010
Approved amount 382'814.00
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Keywords (5)

Candida; antifungal resitance; gene regulation; multidrug transporters; calcineurin

Lay Summary (English)

Lead
Lay summary
Background
Candida albicans is an important cause of fungal infections in immuno-compromised patients but also can affects healthy individuals.
Several antifungal agents (azoles, amphotericin B, echinocandins) are available to fight against C. albicans infections however their efficacy is still dependent on the response of C. albicans to their exposure. C.albicans can respond rapidly to antifungal exposure either by reversible changes in gene transcriptional programs or by engaging resistance mechanisms. These mechanisms enable growth at antifungal drug concentrations that normally inhibit growth of wild-type isolates.
C.albicans can also respond to antifungal exposure by tolerance mechanisms permitting the survival of this yeast even in high drug concentrations.

Aims of the project
The exposure of C. albicans to the class of azoles, which are still the most widely used antifungal agents, illustrates these different responses.
First, our own work has demonstrated that clinical C. albicans isolates acquire resistance to azole by target mutations or by upregulation of multidrug transporter genes (ABC-transporters CDR1/CDR2 and Major Facilitator MDR1). A mutation in a transcription factor (TAC1, for Transcriptional Activator of CDR genes) is responsible for CDR1/CDR2 upregulation. Besides this role in azole resistance, TAC1 is necessary for transient CDR1/CDR2 expression in response to drug exposure. Second, our laboratory has established that the calcium-dependent calcineurin signaling pathway is critical for the survival (or tolerance) of C.albicans to azoles in vitro.
In this research proposal, we will further investigate the two types of response to antifungal agents in C. albicans. First, the molecular basis behind the upregulation of CDR1 and CDR2 by TAC1 will be further elucidated. We plan 1) to identify Tacp1 modifications necessary for the regulation of CDR1/CDR2; 2) to obtain a larger set of mutations in TAC1 alleles conferring transcriptional hyperactivity. Moreover, since theregulator(s) of MDR1 is still unknown, it will be identified a collection of mutants for all putative transcription factors in C. albicans.
Second, the involvement of calcineurin in the tolerance to antifungal drug will be further addressed. In this separate section of the project, we plan 1) to investigate the molecular events (signs of apopotosis or necrosis, calcium fluxes) resulting in the death of C. albicans when exposed to antifungal agents; 2) to obtain by proteomic approaches additional calcineurin targets critical for antifungal tolerance.

Expected value of the project
The results obtained during the completion of this research proposal will greatly enhance our understanding of the response of C. albicans to antifungal agents. The genomic mutations on drug resistance genes resulting from previous and projected results will contribute to design tools for the detection of antifungal resistance. Furthermore, the understanding of antifungal tolerance might open novel possibilities for the design of specific inhibitors.

Web pages: http://www.chuv.ch/imul, http://www.chuv.ch/imul/euresfun
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
100747 Regulation of multidrug transporter genes involved in antifungal resistance in the human pathogen Candida albicans 01.05.2003 Project funding
127378 Regulatory genes of antifungal resistance and their impact on fitness and virulence of pathogenic Candida species 01.03.2010 Project funding

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