P David Rogers
University Of Tennessee Health Sci Ctr
Project start date: 2003-12-01
Project end date: 2017-01-31
Sponsored Links Excellgen http://Excellgen.com
NOVEL AZOLE RESISTANCE MECHANISMS IN CANDIDA ALBICANS
P David Rogers, Associate Professor
University Of Tennessee Health Sci Ctr, 62 S. Dunlap, Suite 300, Memphis, Tn 38163
Grant 2R01AI058145-04A1 from National Institute Of Allergy And Infectious Diseases
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
Keywords: 1H-1, 2, 4-Triazole-1-ethanol, alpha-(2, 4-difluorophenyl)-alpha-(1H-1, 2, 4-triazol-1-ylmethyl)-; ABC20; ABCB1; ABCB1 gene; AIDS; ATP-Binding Cassette, Sub-Family B (MDR/TAP), Member 1 Gene; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Antifungal Agents; Antifungal Drug; Antifungal Drug Resistance; Antifungal Drug Resistant; Antifungal resistant; Antiretroviral Therapy, Highly Active; Azole resistance; Azole resistant; Azoles; C. albicans; C.albicans; C6 Zinc Cluster; Candida albicans; Clinical; Country; Cutaneous; Drug Resistance, Fungal; Drug Therapy; Fluconazole; Fluconazole resistance; Fluconazole resistant; Frequencies (time pattern); Frequency; Fungal Drug Resistance; Fungicides, Therapeutic; Fungus drug resistant; GP170; Gene Targeting; General Transcription Factor Gene; Genes; Goals; HAART; Highly Active Antiretroviral Therapy; Human; Human, General; Immunologic Deficiency Syndrome, Acquired; Infection; MDR-1; MDR1; MDR1 Gene; Man (Taxonomy); Man, Modern; Mediating; Molecular; Opportunistic Infections; Oropharyngeal Candidiasis; P-GP; P-Glycoprotein 1 Gene; PGY1; Patients; Pharmacotherapy; Predisposition; Proteins; Proto-Oncogene, Transcription Factor; Resistance; Resistance Gene-1, Multidrug; Resistance Gene-1s, Multidrug; Resistance development; Resistant development; Susceptibility; Systemic infection; Targetings, Gene; Toxic effect; Toxicities; Transcription factor genes; Treatment Failure; United States; Up-Regulation; Up-Regulation (Physiology); Upregulation; Zinc Cluster; alpha-(2, 4-difluorophenyl)-alpha- (1, 2, 4-triazol-1-ylmethyl)-1, 2, 4- triazole-1-ethanol; anti-fungal; anti-fungal drug resistance; anti-fungal drug resistant; anti-fungal resistance; anti-fungal resistant; anti-retroviral therapy, highly active; antifungal resistance; antifungals; base; cis acting element; developing resistance; diflucan; efflux pump; fungus drug resistance; gain of function mutation; gene product; improved; new approaches; novel; novel approaches; novel strategies; novel strategy; oropharyngeal thrush; pathogen; patient population; resistance mechanism; resistance to anti-fungal; resistance to antifungal; resistance to azole; resistant; resistant mechanism; resistant strain; resistant to anti-fungal; resistant to antifungal; resistant to azole; trait; transcription factor; treatment strategy
Relevance: Candida albicans is an important human fungal pathogen that can develop resistance to the azoles, the most commonly prescribed class of antifungal drugs. This application proposes to understand how this pathogen develops resistance to such antifungal drugs with an ultimate goal of better strategies for treatment of these infections and more rapidly detecting resistance
Project start date: 2003-12-01
Project end date: 2011-04-30
Budget start date: 22-MAY-2009
Budget end date: 30-APR-2010
PFA/PA: PA-07-070
2R01AI058145-04A1 (2009): $369583
Grants awarded to P David Rogers
NOVEL AZOLE RESISTANCE MECHANISMS IN CANDIDA ALBICANS
P David Rogers, Associate Professor
University Of Tennessee Health Sci Ctr, 62 S. Dunlap, Suite 300, Memphis, Tn 38163
Grant 5R01AI058145-05 from National Institute Of Allergy And Infectious Diseases
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
Keywords: 1H-1, 2, 4-Triazole-1-ethanol, alpha-(2, 4-difluorophenyl)-alpha-(1H-1, 2, 4-triazol-1-ylmethyl)-; ABC20; ABCB1; ABCB1 gene; AIDS; ATP-Binding Cassette, Sub-Family B (MDR/TAP), Member 1 Gene; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Alleles; Allelic Loss; Allelomorphs; Amino Acid Substitution; Antifungal Agents; Antifungal Drug; Antifungal Drug Resistance; Antifungal Drug Resistant; Antifungal resistant; Antiretroviral Therapy, Highly Active; Azole resistance; Azole resistant; Azoles; C. albicans; C.albicans; C6 Zinc Cluster; Candida albicans; Cell Communication and Signaling; Cell Signaling; Chromosomes; Clinical; Country; Cutaneous; Drug Resistance, Fungal; Drug Therapy; Drugs; Fluconazole; Fluconazole resistance; Fluconazole resistant; Frequencies (time pattern); Frequency; Fungal Drug Resistance; Fungicides, Therapeutic; Fungus drug resistant; GP170; Gene Expression; Gene Targeting; GeneHomolog; General Transcription Factor Gene; Genes; Genetic Alteration; Genetic Change; Genetic defect; Goals; HAART; Highly Active Antiretroviral Therapy; Homolog; Homologous Gene; Homologue; Human; Human, General; Immunologic Deficiency Syndrome, Acquired; Infection; Intracellular Communication and Signaling; Loss of Heterozygosity; MDR-1; MDR1; MDR1 Gene; Man (Taxonomy); Man, Modern; Mediating; Medication; Molecular; Mutation; NK2; NKA; NKNA; Opportunistic Infections; Oropharyngeal Candidiasis; P-GP; P-Glycoprotein 1 Gene; PGY1; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Proteins; Proto-Oncogene, Transcription Factor; Regulation; Resistance; Resistance Gene-1, Multidrug; Resistance Gene-1s, Multidrug; Resistance development; Resistant development; Role; S cerevisiae; Saccharomyces cerevisiae; Signal Transduction; Signal Transduction Systems; Signaling; Sterols; Susceptibility; Systemic infection; TAC1; TAC1 gene; TAC2; Targetings, Gene; Toxic effect; Toxicities; Transcription factor genes; Treatment Failure; United States; Up-Regulation; Up-Regulation (Physiology); Upregulation; Yeast, Baker`s; Yeast, Brewer`s; Zinc Cluster; alpha-(2, 4-difluorophenyl)-alpha- (1, 2, 4-triazol-1-ylmethyl)-1, 2, 4- triazole-1-ethanol; anti-fungal; anti-fungal drug resistance; anti-fungal drug resistant; anti-fungal resistance; anti-fungal resistant; anti-retroviral therapy, highly active; antifungal resistance; antifungals; base; biological signal transduction; cis acting element; developing resistance; diflucan; drug/agent; efflux pump; fungus drug resistance; gain of function; gain of function mutation; gene product; genome mutation; improved; new approaches; novel; novel approaches; novel strategies; novel strategy; oropharyngeal thrush; overexpression; pathogen; patient population; resistance mechanism; resistance to anti-fungal; resistance to antifungal; resistance to azole; resistant; resistant mechanism; resistant strain; resistant to anti-fungal; resistant to antifungal; resistant to azole; social role; trait; transcription factor; treatment strategy; uptake
Relevance: Candida albicans is an important human fungal pathogen that can develop resistance to the azoles, the most commonly prescribed class of antifungal drugs. This application proposes to understand how this pathogen develops resistance to such antifungal drugs with an ultimate goal of better strategies for treatment of these infections and more rapidly detecting resistance
Project start date: 2003-12-01
Project end date: 2011-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: PA-07-070
5R01AI058145-05 (2010): $370000
1R21AI058145-01A1 (2004): $292000
5R01AI058145-03 (2007): $321661
5R01AI058145-02 (2006): $331717
1R01AI058145-01A2 (2005): $328645