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Eukaryotic Cell, August 2004, p. 932-943, Vol. 3, No. 4
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.4.932-943.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Discovery of Cercosporamide, a Known Antifungal Natural Product, as a Selective Pkc1 Kinase Inhibitor through High-Throughput Screening{dagger}

Andrea Sussman, Karen Huss, Li-Chun Chio, Steve Heidler, Margaret Shaw, Doreen Ma, Guoxin Zhu, Robert M. Campbell, Tae-Sik Park,{ddagger} Palaniappan Kulanthaivel, John E. Scott, John W. Carpenter, Mark A. Strege, Matthew D. Belvo, James R. Swartling, Anthony Fischl, Wu-Kuang Yeh, Chuan Shih, and Xiang S. Ye*

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285

Received 18 March 2004/ Accepted 1 June 2004

The Pkc1-mediated cell wall integrity-signaling pathway is highly conserved in fungi and is essential for fungal growth. We thus explored the potential of targeting the Pkc1 protein kinase for developing broad-spectrum fungicidal antifungal drugs through a Candida albicans Pkc1-based high-throughput screening. We discovered that cercosporamide, a broad-spectrum natural antifungal compound, but previously with an unknown mode of action, is actually a selective and highly potent fungal Pkc1 kinase inhibitor. This finding provides a molecular explanation for previous observations in which Saccharomyces cerevisiae cell wall mutants were found to be highly sensitive to cercosporamide. Indeed, S. cerevisiae mutant cells with reduced Pkc1 kinase activity become hypersensitive to cercosporamide, and this sensitivity can be suppressed under high-osmotic growth conditions. Together, the results demonstrate that cercosporamide acts selectively on Pkc1 kinase and, thus, they provide a molecular mechanism for its antifungal activity. Furthermore, cercosporamide and a ß-1,3-glucan synthase inhibitor echinocandin analog, by targeting two different key components of the cell wall biosynthesis pathway, are highly synergistic in their antifungal activities. The synergistic antifungal activity between Pkc1 kinase and ß-1,3-glucan synthase inhibitors points to a potential highly effective combination therapy to treat fungal infections.

* Corresponding author. Mailing address: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. Phone: (317) 277-1467. Fax: (317) 277-3652. E-mail: Ye_Xiang{at}lilly.com.

{dagger} Supplemental material for this article may be found at http://ec.asm.org.

{ddagger} Present address: Cardiovascular Pharmacology, Pfizer, Ann Arbor, MI 48105.

Eukaryotic Cell, August 2004, p. 932-943, Vol. 3, No. 4
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.4.932-943.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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