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Identification and Functional Ascertainment of the Pneumocystis jirovecii Potential Drug Targets Gsc1 and Kre6 Involved in Glucan Synthesis
Author(s) -
Luraschi Amanda,
Cissé Ousmane H.,
Pagni Marco,
Hauser Philippe M.
Publication year - 2016
Publication title -
journal of eukaryotic microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.067
H-Index - 77
eISSN - 1550-7408
pISSN - 1066-5234
DOI - 10.1111/jeu.12385
Subject(s) - biology , echinocandins , pneumocystis jirovecii , caspofungin , pneumocystis carinii , gene , antifungal drug , microbiology and biotechnology , fungal protein , saccharomyces cerevisiae , genetics , candida albicans , virology , amphotericin b , human immunodeficiency virus (hiv) , antifungal
The most efficient drug against the human pathogenic fungus Pneumocystis jirovecii is cotrimoxazole targeting the folate biosynthesis. However, resistance toward it is emerging and adverse effects occur in some patients. Studies in rodent models suggested that echinocandins could be useful to treat Pneumocystis pneumonia. Echinocandins inhibit the catalytic subunit Gsc1 of the enzymatic complex ensuring the synthesis of 1,3‐β glucan, an essential constituent of cell walls of most fungi. Besides, inhibitors of the enzyme Kre6 involved in the synthesis of 1,6‐β glucan, another essential component of fungal walls, were recently described. We identified and functionally characterized these two potential drug targets in the human pathogen P. jirovecii by rescue of the null allele of the orthologous gene in Saccharomyces cerevisiae . The P. jirovecii proteins Gsc1 and Kre6 identified using those of the relative Pneumocystis carinii as the query sequence showed high sequence identity to the putative fungal orthologs (53–97% in conserved functional domains). The expression of their encoding genes on plasmid rescued the increased sensitivity to, respectively, caspofungin or calcofluor white of the corresponding S. cerevisiae null allele. The uniqueness and likely essentiality of these proteins suggest that they are potential good drug targets.