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Journal of Antimicrobial Chemotherapy (2001) 47, 513-519
© 2001 The British Society for Antimicrobial Chemotherapy

HWY-289, a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans

Kang-Sik Parka, Kap-Chul Kanga, Ki-Young Kima, Pan-Young Jeonga, Jai-Hyun Kima, David J. Adamsb, Jung-Ho Kimc and Young-Ki Paika,*

a Department of Biochemistry, Bioproducts Research Center and Yonsei Proteome Research Center, Yonsei University, 134 Shinchon-dong, Sudaemoon-ku, Seoul, Korea; b Department of Microbiology, University of Leeds, Leeds, UK; c Hanwha Chemical Research and Development Center, Taejeon 305-345, Korea

The antifungal properties of 515 synthetic and semi-synthetic protoberberines were investigated. HWY-289 was chosen for further study because it exhibited the most significant anti-Candida activity (MICs were 1.56 mg/L for Candida albicans and Candida krusei; 6.25 mg/L for Candida guilliermondii) but did not demonstrate toxicity in rats. HWY-289 inhibited the incorporation of L-[methyl-14C]methionine into the C-24 of ergosterol in whole cells of C. albicans (IC50 20 µM). However, HWY-289 (100 µM) had no effect on mammalian cholesterol biosynthesis in rat microsomes while miconazole (100 µM) was a potent inhibitor of cholesterol biosynthesis under identical assay conditions. A second major target site for HWY-289 was identified that involves cell wall biosynthesis in C. albicans. HWY-289 was a potent inhibitor of the chitin synthase isozymes CaCHS1 and CaCHS2, with IC50 values of 22 µM for each enzyme. The effect was highly specific in that HWY-289 had no significant effect on C. albicans CaCHS3 (IC50 > 200 µM). Thus, HWY-289 compared favourably with well-established antifungal agents as an inhibitor of the growth of Candida species in vitro, and may have considerable potential as a new class of antifungal agent that lacks toxic side effects in the human host.

* Correspondence address. Department of Biochemistry, Yonsei University, 134 Shinchon-dong, Sudaemun-ku, Seoul 120-749, Korea. Tel: +82-2-2123-4242/2702; Fax: +82-2-393-6589/362-9897; E-mail: paikyk{at}yonsei.ac.kr


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[Abstract] [Full Text] [PDF]


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