application): While the incidence of fungal infections has escalated significantly, only a limited number of antifungal drugs are currently available for treatment. For this reason, the ultimate objective of the proposed investigation is to identify novel lead compounds for the development of antifungal drugs. To accomplish their goals, the applicants propose five specific aims, namely: (1) exploring novel targets already validated as essential for growth and/or infectivity of Candida albicans in the host, including fatty acid synthase (Fas2p), histidine kinase (Cahk1p), and glucan transferases (Phr1p/Phr2p). In addition, the investigators plan to screen natural product libraries by developing high throughput assays libraries against these targets for discovery and characterization of novel antifungal agents. (2) validating other potential targets for which the corresponding genes have already been obtained, including a second histidine kinase (Cassk1p), and the putative transcriptional/translational regulators, Elf2p and Mot2p. (3) using bioassay-directed fractionation to isolate and purify active constituents from active extracts and determine the structures of purified active compounds, as well as to prioritize active compounds. (4) characterizing pure compounds in in vitro assays in order to determine potency, selectivity, activity spectrum, etc., and prioritize promising leads for further study. (5) determining in vivo efficacy of appropriate compounds in animal models of systemic candidiasis. If efficacious, compounds will also be evaluated in an animal model of aspergillosis. The targets chosen for study are considered to be attractive because either no human homologues are known to exist or because they are readily distinguishable biochemically from the human homologue. The investigation outlined in the application will combine and integrate the complementing strengths of researchers at the Georgetown University (molecular biology/target development, animal models), the University of Mississippi National Center for Development of Natural Products (natural products chemistry/antifungal screening), and Dorlin Pharmaceuticals Inc. (assay development, high throughput screening).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088456-04
Application #
6633859
Study Section
Special Emphasis Panel (ZAI1-VSG-A (S1))
Program Officer
Fu, Yali
Project Start
2000-05-16
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2005-04-30
Support Year
4
Fiscal Year
2003
Total Cost
$643,219
Indirect Cost
Name
Georgetown University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Krom, Bastiaan P; Cohen, Jesse B; McElhaney Feser, Gail E et al. (2007) Optimized candidal biofilm microtiter assay. J Microbiol Methods 68:421-3
Kruppa, Michael; Krom, Bastiaan P; Chauhan, Neeraj et al. (2004) The two-component signal transduction protein Chk1p regulates quorum sensing in Candida albicans. Eukaryot Cell 3:1062-5
Krueger, Karl E; Ghosh, Anup K; Krom, Bastiaan P et al. (2004) Deletion of the NOT4 gene impairs hyphal development and pathogenicity in Candida albicans. Microbiology 150:229-40
Zhang, Zhizhen; ElSohly, Hala N; Li, Xing-Cong et al. (2003) Flavanone glycosides from Miconia trailii. J Nat Prod 66:39-41
Zhang, Zhizhen; ElSohly, Hala N; Li, Xing-Cong et al. (2003) Phenolic compounds from Nymphaea odorata. J Nat Prod 66:548-50
Laakso, Jodi A; Raulli, Robert; McElhaney-Feser, Gail E et al. (2003) CT2108A and B: New fatty acid synthase inhibitors as antifungal agents. J Nat Prod 66:1041-6
Kruppa, Michael; Goins, Tresa; Cutler, Jim E et al. (2003) The role of the Candida albicans histidine kinase [CHK1) gene in the regulation of cell wall mannan and glucan biosynthesis. FEMS Yeast Res 3:289-99
Li, Xing-Cong; Joshi, Alpana S; ElSohly, Hala N et al. (2002) Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies. J Nat Prod 65:1909-14
Zhao, X J; Calderone, R A; Krueger, K E et al. (2001) Isolation and characterization of the Candida albicans MOT2 gene. Med Mycol 39:81-6