Medicinal genetics approach towards identifying the molecular target of a novel inhibitor of fungal cell wall assembly

Summary Glycosylphosphatidylinositol (GPI)‐anchored cell wall mannoproteins are required for the adhesion of pathogenic fungi, such as Candida albicans, to human epithelium. Small molecular inhibitors of the cell surface presentation of GPI‐anchored mannoproteins would be promising candidate drugs t...

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Published in:Molecular microbiology 2003-05, Vol.48 (4), p.1029-1042
Main Authors: Tsukahara, Kappei, Hata, Katsura, Nakamoto, Kazutaka, Sagane, Koji, Watanabe, Nao‐aki, Kuromitsu, Junro, Kai, Junko, Tsuchiya, Mamiko, Ohba, Fuminori, Jigami, Yoshifumi, Yoshimatsu, Kentaro, Nagasu, Takeshi
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Candida albicans - drug effects
Candida albicans - metabolism
Cell Adhesion
Cell Wall - drug effects
Cell Wall - metabolism
Glycosylphosphatidylinositols - biosynthesis
Glycosylphosphatidylinositols - metabolism
Inositol - metabolism
Isoquinolines - pharmacology
Molecular Sequence Data
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
Saccharomyces cerevisiae Proteins - physiology
Sequence Homology, Amino Acid
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Summary:Summary Glycosylphosphatidylinositol (GPI)‐anchored cell wall mannoproteins are required for the adhesion of pathogenic fungi, such as Candida albicans, to human epithelium. Small molecular inhibitors of the cell surface presentation of GPI‐anchored mannoproteins would be promising candidate drugs to block the establishment of fungal infections. Here, we describe a medicinal genetics approach to identifying the gene encoding a novel target protein that is required for the localization of GPI‐anchored cell wall mannoproteins. By means of a yeast cell‐based screening procedure, we discovered a compound, 1‐[4‐butylbenzyl]isoquinoline (BIQ), that inhibits cell wall localization of GPI‐anchored mannoproteins in Saccharomyces cerevisiae. Treatment of C. albicans cells with this compound resulted in reduced adherence to a rat intestine epithelial cell monolayer. A previously uncharacterized gene YJL091c, named GWT1, was cloned as a dosage‐dependent suppressor of the BIQ‐induced phenotypes. GWT1 knock‐out cells showed similar phenotypes to BIQ‐treated wild‐type cells in terms of cell wall structure and transcriptional profiles. Two different mutants resistant to BIQ each contained a single missense mutation in the coding region of the GWT1 gene. These results all suggest that the GWT1 gene product is the primary target of the compound.
ISSN:0950-382X
1365-2958
DOI:10.1046/j.1365-2958.2003.03481.x