Fungi are amazing organisms for they are able to use almost any surface for growth, e.g., bathroom tile, skin. Unfortunately, they also are wonderful at colonizing and using plants, humans and animals as substrates. During the last two decades the incidence of fungal infections, especially involving immunocompromised patients, has dramatically increased. This is in part due to the tremendous advances in medicine that permit the saving of patients with neoplastic and immunocompromising diseases that would overwise not have survived. It is ironic that many of these triumphs to modern medicine succumb to fungal infections for which there are few or no drugs available for treatment. The fungal cell wall protects the organism against a hostile environment and relays signals for invasion and infection of a likely plant, animal, or human host. The cell wall of filamentous fungi is synthesized at each hyphal apex in a complex assembly sequence. For example, the wall of Neurospora crassa and the filamentous form of Candida albicans is primarily composed of chitin embedded in a protein matrix and (1-3)beta- D-glucan. Current drug discovery programs at many pharmaceutical companies target the cell-wall polymer synthetic enzymes glucan and chitin synthases as well as ergosterol biosynthesis. While ergosterol biosynthesis inhibitors have been clinically effective, disappointingly, few compounds that target cell-wall polymer synthesis have been found; none is currently in clinical use. This observation has been a major surprise given the vast success with bacterial cell-wall inhibitors. There appears to be general consensus among workers that new cell-wall targets are needed for the development of novel antifungal compounds. We propose to identify and characterize a number of genes which play essential and necessary roles in cell-wall assembly of the model fungus, Neurospora crassa. We will continue with our current work concerning (1,3)beta-glucan synthase and expand our study to include three cell- wall assembly genes, cwa-1 and -2 and osmotic-1. We will isolate each gene by functional complementation of our unique set of cell-wall-less mutants. Each gene will be sequenced, the predicted amino acid sequence determined and data bases searched to identify similarities with other genes and proteins. We will use the isolated N.crassa genes as probes to isolate and characterize cognate genes the human pathogens, Candida albicans and Aspergillus fumigatus. It is likely that the glucan synthase and cell-wall assembly genes represent novel targets for antifungal drugs.
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| Miller, Tamara K; Renault, Samantha; Selitrennikoff, Claude P (2002) Molecular dissection of alleles of the osmotic-1 locus of Neurospora crassa. Fungal Genet Biol 35:147-55 |
| Selitrennikoff, C P; Alex, L; Miller, T K et al. (2001) COS-l, a putative two-component histidine kinase of Candida albicans, is an in vivo virulence factor. Med Mycol 39:69-74 |
| Pott, G B; Miller, T K; Bartlett, J A et al. (2000) The isolation of FOS-1, a gene encoding a putative two-component histidine kinase from Aspergillus fumigatus. Fungal Genet Biol 31:55-67 |
