Candida albicans is a pathogenic yeast that causes serious fungal infections in the immunocompromised and opponunistic Candida infections can be the first indication of immunosuppression in HIV+ individuals. AIDS patients frequently suffer from oropharyngeal candidiasis (OPC) and require antifungal therapy. In the 1990s there was a dramatic increase in the failure of fluconazole therapy for AIDS patients with OPC due to C. albicans strains developing fluconazole resistance. The most common mechanism responsible for high level fluconazole resistance in these yeast was over-expression of drug efflux pump Cdrl p. Globally, OFC remains a major opponunistic infection in HIVIAIDS, and the widespread use of fluconazole in the third world is likely to maintain pressure on C. albicans to develop resistance. The overall objective of this research is to use a novel strategy to improve the treatment of AIDS patients with oral candidiasis by combating azoleresistance in C. albicans. Specific objectives are to: ? ? 1. Employ a novel heterologous functional hyper-expression system to determine the mechanism of pumping by Cdrl p, using both in vitro mutagenized Cdrl p and Cdrl proteins from clinical C. albicans isolates (obtained from AIDS patients) that demonstrate high and low pump activities. ? ? 2. Use the heterologous functional hyper-expression of Cdrlp to screen a unique combinatorial Doctapeptide library for peptides that inhibit the pump. ? ? This work will validate a novel approach to combating azole-resistance in C. albicana An understanding of drug pumping mechanisms may indicate new ways to circumvent efflux-mediated resistance. This project is expected to identify a lead compound with the potential to sensitize resistant strains to azole antifungals. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DE015075-01
Application #
6594303
Study Section
Special Emphasis Panel (ZDE1-YL (70))
Program Officer
Nokta, Mostafa A
Project Start
2002-12-01
Project End
2004-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$133,462
Indirect Cost
Name
University of Otago
Department
Type
DUNS #
590135182
City
Dunedin
State
Country
New Zealand
Zip Code
9054
Keniya, Mikhail V; Cannon, Richard D; Nguy?n, ÂnBình et al. (2013) Heterologous expression of Candida albicans Pma1p in Saccharomyces cerevisiae. FEMS Yeast Res 13:302-11
Niimi, Kyoko; Harding, David R K; Holmes, Ann R et al. (2012) Specific interactions between the Candida albicans ABC transporter Cdr1p ectodomain and a D-octapeptide derivative inhibitor. Mol Microbiol 85:747-67
Lamping, Erwin; Cannon, Richard D (2010) Use of a yeast-based membrane protein expression technology to overexpress drug resistance efflux pumps. Methods Mol Biol 666:219-50
Lamping, Erwin; Ranchod, Amrita; Nakamura, Kenjirou et al. (2009) Abc1p is a multidrug efflux transporter that tips the balance in favor of innate azole resistance in Candida krusei. Antimicrob Agents Chemother 53:354-69
Holmes, Ann R; Lin, Ya-Hsun; Niimi, Kyoko et al. (2008) ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates. Antimicrob Agents Chemother 52:3851-62
Lamping, Erwin; Monk, Brian C; Niimi, Kyoko et al. (2007) Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryot Cell 6:1150-65
Holmes, Ann R; Tsao, Sarah; Ong, Soo-Wee et al. (2006) Heterozygosity and functional allelic variation in the Candida albicans efflux pump genes CDR1 and CDR2. Mol Microbiol 62:170-86
Holmes, Ann R; Tsao, Sarah; Lamping, Erwin et al. (2006) Amino acid residues affecting drug pump function in Candida albicans--C. albicans drug pump function. Nippon Ishinkin Gakkai Zasshi 47:275-81
Niimi, K; Maki, K; Ikeda, F et al. (2006) Overexpression of Candida albicans CDR1, CDR2, or MDR1 does not produce significant changes in echinocandin susceptibility. Antimicrob Agents Chemother 50:1148-55
Monk, Brian C; Niimi, Kyoko; Lin, Susan et al. (2005) Surface-active fungicidal D-peptide inhibitors of the plasma membrane proton pump that block azole resistance. Antimicrob Agents Chemother 49:57-70

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