Department of Cell and Developmental Biology (CDB)

Fungal Cell-Wall Assembly

Research in my laboratory centers around determining the molecular mechanisms for cell-wall assembly in human pathogenic fungi. Perhaps the most striking difference between fungal cells and human cells is that fungal cells are encased in a cell wall. The cell wall is not an inert outer layer, but rather plays a dynamic role in all aspects of fungal physiology, e.g., morphogenesis, metabolite transport, protein secretion, signaling, and cell-cell contact.The fact that human cells lack not only a cell wall, but also the genetic and biosynthetic machinery to make the wall, suggest that drugs that target fungal cell-wall synthesis will be safe and specific antifungals.

Current research in the laboratory has expanded to include:

1. The determination of the molecular mechanism of Cryptococcus neoformans resistance to the echinocandin class (β-glucan synthase inhibitor) of antifungals. We have excluded the target, glucan synthase, and efflux pumps as being the mechanism and are focusing on cell-wall components and drug degradation pathways as being involved.
2. The development and deployment of therapeutic and prophylactic vaccines to treat and prevent infections due to Coccidioides immitis, Aspergillus fumigatus and Cryptococcus neoformans. We are using the common baker’s yeast containing and expressing virulence genes and proteins as a delivery vehicle. Animal models have shown that our vaccine technology is highly protective against infection by each of these fungi.
3. The discovery of novel antifungal compounds using a strain of Neurospora crassa that grows and divides without a cell wall.  We have screened compound libraries and have identified over 100 “hits”. We have characterized only a few of these compounds.
4. In collaboration with Colorado State University Scientists, our laboratory is developing methods to screen for novel compounds that can be used to prevent or treat infections caused by Leishmania major, the causative organism responsible for leishmaniasis. We have developed a strain of yeast that requires an essential L. major enzyme for growth and are currently screening compound libraries in search of inhibitors.

Selected Publications: (from 97 and 12 patents)

Borkovich, K, Alex, L., Yarden, O., et al. Lessons from the genome sequence of Neurospora crassa: Tracing the path from genomic blueprint to multicellular organism. Microbio. Molec. Biol. Rev. 68:1-108. 2004.

Maligie, M.B., and C. P. Selitrennikoff. Cryptococcus neoformans resistance to echinocandins: characterization and optimization of in vitro assay conditions for (1,3)β-glucan synthase activity. Antimicrob. Agents. Chemo. 49: 2851-2856. 2005.

Gerik, K, Donlin, M., Soto, C., Banks, A., Banks, I., Maligie, M., Selitrennikoff, C.P. and Jennifer K. Lodge. Cell wall integrity is dependent on the PKC1 signal transduction pathway in Cryptococcus neoformans. Molec. Microbiol. 58: 393-408. 2005

Latest Publications in PubMed