title: Discovery of a small-molecule inhibitor of {beta}-1,6-glucan synthesis.
abstract: 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.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan. kitamura.akihiro.cr@daiichisankyo.co.jp
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kitamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Someya
authors.forename: Masato
authors.initials: M
authors.lastname: Hata
authors.forename: Ryohei
authors.initials: R
authors.lastname: Nakajima
authors.forename: Makoto
authors.initials: M
authors.lastname: Takemura
mesh_terms: D019342:Acetic Acid / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics; D005658:Fungi / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D011725:Pyridines / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D014529:Uridine / Q000378:metabolism; D047071:beta-Glucans / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C539939:D75-4590; D011725:Pyridines; D047071:beta-Glucans; C064197:beta-1,6-glucan; D007930:Leucine; D005947:Glucose; D019342:Acetic Acid; D014529:Uridine