Effect of beta-1,6-glucan inhibitors on the invasion process of Candida albicans: potential mechanism of their in vivo efficacy.
Beta-1,6-glucan is a fungus-specific cell wall component that is essential for the retention of many cell wall proteins. We recently reported the discovery of a small molecule inhibitor of beta-1,6-glucan biosynthesis in yeasts. In the course of our study of its derivatives, we found a unique feature in their antifungal profile. D21-6076, one of these compounds, exhibited potent in vitro and in vivo antifungal activities against Candida glabrata. Interestingly, although it only weakly reduced the growth of Candida albicans in conventional media, it significantly prolonged the survival of mice infected by the pathogen. Biochemical evaluation of D21-6076 indicated that it inhibited beta-1,6-glucan synthesis of C. albicans, leading the cell wall proteins, which play a critical role in its virulence, to be released from the cell. Correspondingly, adhesion of C. albicans cells to mammalian cells and their hyphal elongation were strongly reduced by the drug treatment. The results of the experiment using an in vitro model of vaginal candidiasis showed that D21-6076 strongly inhibited the invasion process of C. albicans without a significant reduction in its growth in the medium. These evidences suggested that D21-6076 probably exhibited in vivo efficacy against C. albicans by inhibiting its invasion process.
Kitamura
Akihiro
A
R&D Planning Department, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. kitamura.akihiro.cr@daiichisankyo.co.jp
Higuchi
Saito
S
Hata
Masato
M
Kawakami
Katsuhiro
K
Yoshida
Kumi
K
Namba
Kenji
K
Nakajima
Ryohei
R
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000648:ultrastructure; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D053586:Virus Internalization / Q000187:drug effects*; D047071:beta-Glucans / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000935:Antifungal Agents; D047071:beta-Glucans; C064197:beta-1,6-glucan