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Antimicrobial Agents and Chemotherapy, September 2009, p. 3963-3971, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00435-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Effect of β-1,6-Glucan Inhibitors on the Invasion Process of Candida albicans: Potential Mechanism of Their In Vivo Efficacy {triangledown}

Akihiro Kitamura,* Saito Higuchi, Masato Hata, Katsuhiro Kawakami, Kumi Yoshida, Kenji Namba, and Ryohei Nakajima

R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

Received 31 March 2009/ Returned for modification 29 May 2009/ Accepted 5 July 2009

β-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 β-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 β-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.

* Corresponding author. Mailing address: R&D Planning Department, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Phone: 3-5740-3498. Fax: 3-5436-8588. E-mail: kitamura.akihiro.cr{at}daiichisankyo.co.jp

{triangledown} Published ahead of print on 13 July 2009.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3963-3971, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00435-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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