Novel Azole Resistance Mechanisms in Candida albicans

Summary

Principal Investigator: P Rogers
Affiliation: University of Tennessee
Country: USA
Abstract: C. albicans is an opportunistic human fungal pathogen that causes mucosal, cutaneous, and systemic infections including oropharyngeal candidiasis (OPC), the most frequent opportunistic infection among patients suffering from AIDS. Fluconazole and other azole antifungal agents have proven effective in the management of OPC;however, with increased use of these agents, treatment failures have occurred that have been associated with the emergence of azole-resistant strains of C. albicans. While the use of highly active antiretroviral therapy (HAART) has reduced the frequency of OPC among AIDS patients in the United States, limited access to such therapy in underdeveloped countries, poor compliance, and toxicity associated with HAART will likely contribute to an increase in this problem among AIDS patients world-wide. While several mechanisms of azole resistance have been described, these are not sufficient to explain this trait in many clinical isolates. We have discovered MRR1 which encodes the transcriptional regulator of the MDR1 efflux pump gene and is a central regulator or azole antifungal resistance in C. albicans. Gain-of-function mutations in the MRR1 gene result in the constitutive activation of this transcription factor, up-regulation of MDR1, and increased fluconazole resistance. The specific aims outlined in the current proposal represent the next steps towards achieving our overall goal of understanding how Mrr1p influences azole resistance in C. albicans. We will identify direct and indirect target genes of Mrr1p, elucidate their cis-acting elements, and determine which of these genes influence Mrr1p-mediated azole resistance. We will also identify accessory proteins that associate with Mrr1p and determine if these accessory proteins influence Mrr1p-mediated azole resistance. These studies will further elucidate the molecular basis for azole antifungal resistance and will ultimately point to novel strategies for predicting treatment failure, overcoming azole resistance, and improving antifungal pharmacotherapy in this patient population.
Funding Period: ----------------2003 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Genome-wide expression and location analyses of the Candida albicans Tac1p regulon
    Teresa T Liu
    Department of Clinical Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    Eukaryot Cell 6:2122-38. 2007
  2. pmc Gain-of-function mutations in UPC2 are a frequent cause of ERG11 upregulation in azole-resistant clinical isolates of Candida albicans
    Stephanie A Flowers
    Department of Clinical Pharmacy, University of Tennessee Health Sciences Center, Memphis, TN, USA
    Eukaryot Cell 11:1289-99. 2012
  3. pmc Mitochondrial two-component signaling systems in Candida albicans
    John Mavrianos
    Public Health Research Institute, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
    Eukaryot Cell 12:913-22. 2013
  4. pmc Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains
    Nico Dunkel
    Institut für Molekulare Infektionsbiologie, Universitat Wurzburg, Wurzburg, Germany
    Mol Microbiol 69:827-40. 2008
  5. doi Transcriptome profile of the vascular endothelial cell response to Candida albicans
    Katherine S Barker
    Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, University of Memphis, Tennessee, USA
    J Infect Dis 198:193-202. 2008
  6. pmc A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate
    Nico Dunkel
    Institut für Molekulare Infektionsbiologie, Universitat Wurzburg, Rontgenring 11, D 97070 Wurzburg, Germany
    Eukaryot Cell 7:1180-90. 2008
  7. pmc The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans
    Joachim Morschhäuser
    Institut für Molekulare Infektionsbiologie, Universitat Wurzburg, Wurzburg, Germany
    PLoS Pathog 3:e164. 2007
  8. pmc Changes in the proteome of Candida albicans in response to azole, polyene, and echinocandin antifungal agents
    Christopher F Hoehamer
    Department of Clinical Pharmacy, Colleges of Pharmacy and Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    Antimicrob Agents Chemother 54:1655-64. 2010
  9. pmc Genomewide expression profile analysis of the Candida glabrata Pdr1 regulon
    Kelly E Caudle
    Children s Foundation Research Center, Le Bonheur Children s Hospital, 50 North Dunlap Street, Memphis, TN 38103, USA
    Eukaryot Cell 10:373-83. 2011
  10. pmc Identification of the Candida albicans Cap1p regulon
    Sadri Znaidi
    Institute for Research in Immunology and Cancer, Universite de Montreal, P O Box 6128, Station Centre Ville, Montreal, Quebec, Canada H3C 3J7
    Eukaryot Cell 8:806-20. 2009

Detail Information

Publications10

  1. pmc Genome-wide expression and location analyses of the Candida albicans Tac1p regulon
    Teresa T Liu
    Department of Clinical Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    Eukaryot Cell 6:2122-38. 2007
    ..They also suggest roles for Tac1p in regulating lipid metabolism (mobilization and trafficking) and oxidative stress response in C. albicans...
  2. pmc Gain-of-function mutations in UPC2 are a frequent cause of ERG11 upregulation in azole-resistant clinical isolates of Candida albicans
    Stephanie A Flowers
    Department of Clinical Pharmacy, University of Tennessee Health Sciences Center, Memphis, TN, USA
    Eukaryot Cell 11:1289-99. 2012
    ..albicans...
  3. pmc Mitochondrial two-component signaling systems in Candida albicans
    John Mavrianos
    Public Health Research Institute, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
    Eukaryot Cell 12:913-22. 2013
    ..albicans possesses a two-component response regulator protein that has survived in mitochondria and regulates a subset of genes whose functions are associated with the oxidative stress response and programmed cell death (apoptosis)...
  4. pmc Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains
    Nico Dunkel
    Institut für Molekulare Infektionsbiologie, Universitat Wurzburg, Wurzburg, Germany
    Mol Microbiol 69:827-40. 2008
    ..albicans...
  5. doi Transcriptome profile of the vascular endothelial cell response to Candida albicans
    Katherine S Barker
    Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, University of Memphis, Tennessee, USA
    J Infect Dis 198:193-202. 2008
    ..During hematogenously disseminated candidiasis, bloodborne Candida albicans interacts with vascular endothelial cells (ECs), which have the capacity to influence the local inflammatory response to this organism...
  6. pmc A gain-of-function mutation in the transcription factor Upc2p causes upregulation of ergosterol biosynthesis genes and increased fluconazole resistance in a clinical Candida albicans isolate
    Nico Dunkel
    Institut für Molekulare Infektionsbiologie, Universitat Wurzburg, Rontgenring 11, D 97070 Wurzburg, Germany
    Eukaryot Cell 7:1180-90. 2008
    ..Here we show for the first time that a gain-of-function mutation in UPC2 leads to the increased expression of ERG11 and imparts resistance to fluconazole in clinical isolates of C. albicans...
  7. pmc The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans
    Joachim Morschhäuser
    Institut für Molekulare Infektionsbiologie, Universitat Wurzburg, Wurzburg, Germany
    PLoS Pathog 3:e164. 2007
    ..albicans isolates and result in constitutive activity of this trancription factor provide detailed insights into the molecular basis of multidrug resistance in this important human fungal pathogen...
  8. pmc Changes in the proteome of Candida albicans in response to azole, polyene, and echinocandin antifungal agents
    Christopher F Hoehamer
    Department of Clinical Pharmacy, Colleges of Pharmacy and Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
    Antimicrob Agents Chemother 54:1655-64. 2010
    ..Some of these antifungal-responsive proteins may represent potential targets for the development of novel therapeutics that could enhance the antifungal activities of these drugs...
  9. pmc Genomewide expression profile analysis of the Candida glabrata Pdr1 regulon
    Kelly E Caudle
    Children s Foundation Research Center, Le Bonheur Children s Hospital, 50 North Dunlap Street, Memphis, TN 38103, USA
    Eukaryot Cell 10:373-83. 2011
    ..Our results demonstrate that while CgPdr1 activates a broad repertoire of genes, specific activating mutations result in the activation of discrete subsets of this repertoire...
  10. pmc Identification of the Candida albicans Cap1p regulon
    Sadri Znaidi
    Institute for Research in Immunology and Cancer, Universite de Montreal, P O Box 6128, Station Centre Ville, Montreal, Quebec, Canada H3C 3J7
    Eukaryot Cell 8:806-20. 2009
    ..Finally, transcriptome analyses showed that increased expression generally accompanies Cap1p binding at its targets, indicating that Cap1p functions as a transcriptional activator...