Document Detail


Discovery of a small-molecule inhibitor of {beta}-1,6-glucan synthesis.
MedLine Citation:
PMID:  19015325     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
It is possible that antifungal drugs with novel modes of action will provide favorable options to treat fungal infections. In the course of our screening for antifungal compounds acting on the cell wall, a pyridobenzimidazole derivative with unique activities, named D75-4590, was discovered. During treatment of Saccharomyces cerevisiae with D75-4590, (i) incorporation of [(14)C]glucose into the beta-1,6-glucan component was selectively reduced, (ii) proteins released from the cell had lost the beta-1,6-glucan moiety, and (iii) cells tended to clump, resulting in impaired cell growth. Genetic analysis of a D75-4590-resistant mutant of S. cerevisiae indicated that its primary target was Kre6p, which is considered to be one of the beta-1,6-glucan synthases. These results strongly suggest that D75-4590 is a specific inhibitor of beta-1,6-glucan synthesis. D75-4590 showed potent activities against various Candida species. It inhibited hyphal elongation of C. albicans as well. KRE6 is conserved in various fungi, but no homologue has been found in mammalian cells. These lines of evidence indicate that D75-4590 is a promising lead compound for novel antifungal drugs. To our knowledge, this is the first report of a beta-1,6-glucan inhibitor.
Authors:
Akihiro Kitamura; Kazuhiko Someya; Masato Hata; Ryohei Nakajima; Makoto Takemura
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Publication Detail:
Type:  Journal Article     Date:  2008-11-17
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  53     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-01-23     Completed Date:  2009-04-20     Revised Date:  2013-06-04    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  670-7     Citation Subset:  IM    
Affiliation:
R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan. kitamura.akihiro.cr@daiichisankyo.co.jp
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MeSH Terms
Descriptor/Qualifier:
Acetic Acid / metabolism
Anti-Bacterial Agents / pharmacology
Antifungal Agents / pharmacology*
Antineoplastic Agents / pharmacology
Benzimidazoles / pharmacology*
Blotting, Western
Cell Wall / drug effects,  metabolism
Drug Resistance, Fungal / genetics
Fungi / drug effects
Glucose / metabolism
Leucine / metabolism
Microbial Sensitivity Tests
Pyridines / pharmacology*
Saccharomyces cerevisiae / drug effects
Uridine / metabolism
beta-Glucans / antagonists & inhibitors*,  metabolism*
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Antifungal Agents; 0/Antineoplastic Agents; 0/Benzimidazoles; 0/D75-4590; 0/Pyridines; 0/beta-Glucans; 37361-00-5/beta-1,6-glucan; 50-99-7/Glucose; 58-96-8/Uridine; 61-90-5/Leucine; 64-19-7/Acetic Acid
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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