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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058145-05
Application #
7847583
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Duncan, Rory A
Project Start
2003-12-01
Project End
2011-10-30
Budget Start
2010-05-01
Budget End
2011-10-30
Support Year
5
Fiscal Year
2010
Total Cost
$370,000
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Rybak, Jeffrey M; Dickens, C Michael; Parker, Josie E et al. (2017) Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis. Antimicrob Agents Chemother 61:
Peters, Brian M; Luna-Tapia, Arturo; Tournu, Hélène et al. (2017) An Azole-Tolerant Endosomal Trafficking Mutant of Candida albicans Is Susceptible to Azole Treatment in a Mouse Model of Vaginal Candidiasis. Antimicrob Agents Chemother 61:
Popp, Christina; Hampe, Irene A I; Hertlein, Tobias et al. (2017) Competitive Fitness of Fluconazole-Resistant Clinical Candida albicans Strains. Antimicrob Agents Chemother 61:
Whaley, Sarah G; Tsao, Sarah; Weber, Sandra et al. (2016) The RTA3 Gene, Encoding a Putative Lipid Translocase, Influences the Susceptibility of Candida albicans to Fluconazole. Antimicrob Agents Chemother 60:6060-6
Berkow, Elizabeth L; Manigaba, Kayihura; Parker, Josie E et al. (2015) Multidrug Transporters and Alterations in Sterol Biosynthesis Contribute to Azole Antifungal Resistance in Candida parapsilosis. Antimicrob Agents Chemother 59:5942-50
Rybak, Jeffrey M; Marx, Kayleigh R; Nishimoto, Andrew T et al. (2015) Isavuconazole: Pharmacology, Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent. Pharmacotherapy 35:1037-51
Flowers, Stephanie A; Colón, Brendan; Whaley, Sarah G et al. (2015) Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans. Antimicrob Agents Chemother 59:450-60
Cowen, Leah E; Sanglard, Dominique; Howard, Susan J et al. (2014) Mechanisms of Antifungal Drug Resistance. Cold Spring Harb Perspect Med 5:a019752
Ramírez-Zavala, Bernardo; Mogavero, Selene; Schöller, Eva et al. (2014) SAGA/ADA complex subunit Ada2 is required for Cap1- but not Mrr1-mediated upregulation of the Candida albicans multidrug efflux pump MDR1. Antimicrob Agents Chemother 58:5102-10
Blankenship, Jill R; Cheng, Shaoji; Woolford, Carol A et al. (2014) Mutational analysis of essential septins reveals a role for septin-mediated signaling in filamentation. Eukaryot Cell 13:1403-10

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