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Antimicrobial Agents and Chemotherapy, February 2009, p. 670-677, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00844-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Discovery of a Small-Molecule Inhibitor of β-1,6-Glucan Synthesis{triangledown}

Akihiro Kitamura,* Kazuhiko Someya, Masato Hata, Ryohei Nakajima, and Makoto Takemura

R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan

Received 26 June 2008/ Returned for modification 16 September 2008/ Accepted 6 November 2008

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 [14C]glucose into the β-1,6-glucan component was selectively reduced, (ii) proteins released from the cell had lost the β-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 β-1,6-glucan synthases. These results strongly suggest that D75-4590 is a specific inhibitor of β-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 β-1,6-glucan inhibitor.

* Corresponding author. Mailing address: R&D Operations 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 17 November 2008.

Antimicrobial Agents and Chemotherapy, February 2009, p. 670-677, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00844-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kitamura, A., Higuchi, S., Hata, M., Kawakami, K., Yoshida, K., Namba, K., Nakajima, R. (2009). Effect of {beta}-1,6-Glucan Inhibitors on the Invasion Process of Candida albicans: Potential Mechanism of Their In Vivo Efficacy. Antimicrob. Agents Chemother. 53: 3963-3971 [Abstract] [Full Text]  


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