Identification and Functional Ascertainment of the Pneumocystis jirovecii Potential Drug Targets Gsc1 and Kre6 Involved in Glucan Synthesis.

Details

Ressource 1Download: 5_27859907_Postprint.pdf (1200.91 [Ko])
State: Public
Version: Author's accepted manuscript
Serval ID
serval:BIB_03F06764D981
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Identification and Functional Ascertainment of the Pneumocystis jirovecii Potential Drug Targets Gsc1 and Kre6 Involved in Glucan Synthesis.
Journal
The Journal of eukaryotic microbiology
Author(s)
Luraschi A., Cissé O.H., Pagni M., Hauser P.M.
ISSN
1550-7408 (Electronic)
ISSN-L
1066-5234
Publication state
Published
Issued date
07/2017
Peer-reviewed
Oui
Volume
64
Number
4
Pages
481-490
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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.

Keywords
Cell wall, Saccharomyces cerevisiae heterologous complementation, echinocandins, human pathogen, pathogenic fungus
Pubmed
Web of science
Open Access
Yes
Create date
05/12/2016 21:53
Last modification date
20/08/2019 12:25
Usage data