Candida albicans is the leading fungal pathogen of humans, causing life-threatening infection in immunocompromised individuals. Treatment of candidiasis is hampered by the limited number of antifungal drugs. The triazoles are the largest class of antifungal drugs in clinical use. They inhibit lanosterol 14-demethylase (Erg11). The therapeutic efficacy of triazoles is compromised by the emergence of drug resistant strains. C. albicans can acquire triazole resistance by multiple distinct mechanisms, including mechanisms to cope with drug-induced cellular stresses. Upc2, a transcriptional regulator of ergosterol biosynthesis pathway genes, is critical for resistance to triazoles. We find that Cph2 is also a regulator of ergosterol biosynthesis and misregulation of Cph2 leads to altered drug sensitivity. How Upc2 and Cph2 are regulated in C. albicans is unclear. Here we propose to use chemical approaches to dissect regulatory mechanisms for Cph2 and Upc2.
Aim 1 identifies small molecules that target transcriptional regulation of ergosterol homeostasis.
Aim 2 identifies protein targets of selected hit compounds in C. albicans by chemical genomics approaches.
Aim 3 will be target verification and functional characterization in C. albicans. Identification of smal molecules and their targets will lead to the discovery of novel pathways and mechanisms that control ergosterol homeostasis and triazole resistance.

Public Health Relevance

Candida has emerged as a significant human pathogen, causing life-threatening infection in immunocompromised individuals. Treatment of candidiasis is hampered by the limited number of antifungal drugs and the emergence of drug resistance. Development of novel combinatory drug therapy will help fight against Candida infections and lower the level of drug toxicity to people.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI099190-04
Application #
8831447
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Duncan, Rory A
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Wang, Xiongjun; Zhu, Wencheng; Chang, Peng et al. (2018) Merge and separation of NuA4 and SWR1 complexes control cell fate plasticity in Candida albicans. Cell Discov 4:45
Mood, Aaron D; Premachandra, Ilandari Dewage Udara Anulal; Hiew, Stanley et al. (2017) Potent Antifungal Synergy of Phthalazinone and Isoquinolones with Azoles Against Candida albicans. ACS Med Chem Lett 8:168-173
Su, Chang; Lu, Yang; Liu, Haoping (2016) N-acetylglucosamine sensing by a GCN5-related N-acetyltransferase induces transcription via chromatin histone acetylation in fungi. Nat Commun 7:12916
Yan, Minghui; Nie, Xinyi; Wang, Huafeng et al. (2015) SUMOylation of Wor1 by a novel SUMO E3 ligase controls cell fate in Candida albicans. Mol Microbiol 98:69-89
Guan, Zhiyun; Liu, Haoping (2015) The WOR1 5' untranslated region regulates white-opaque switching in Candida albicans by reducing translational efficiency. Mol Microbiol 97:125-38
Premachandra, Ilandari Dewage Udara Anulal; Scott, Kevin A; Shen, Chengtian et al. (2015) Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans. ChemMedChem 10:1672-86
Lane, Shelley; Di Lena, Pietro; Tormanen, Kati et al. (2015) Function and Regulation of Cph2 in Candida albicans. Eukaryot Cell 14:1114-26
Guan, Zhiyun; Liu, Haoping (2015) Overlapping Functions between SWR1 Deletion and H3K56 Acetylation in Candida albicans. Eukaryot Cell 14:578-87
Lu, Yang; Su, Chang; Liu, Haoping (2014) Candida albicans hyphal initiation and elongation. Trends Microbiol 22:707-14
Yu, Clinton; Kandur, Wynne; Kao, Athit et al. (2014) Developing new isotope-coded mass spectrometry-cleavable cross-linkers for elucidating protein structures. Anal Chem 86:2099-106

Showing the most recent 10 out of 15 publications