title: HWY-289, a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans.
abstract: 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-(14)C]methionine into the C-24 of ergosterol in whole cells of C. albicans (IC(50) 20 microM). However, HWY-289 (100 microM) had no effect on mammalian cholesterol biosynthesis in rat microsomes while miconazole (100 microM) 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 IC(50) values of 22 microM for each enzyme. The effect was highly specific in that HWY-289 had no significant effect on C. albicans CaCHS3 (IC(50) > 200 microM). 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.
authors.affiliation: Department of Biochemistry, Bioproducts Research Center and Yonsei Proteome Research Center, Yonsei University, 134 Shinchon-dong, Sudaemoon-ku, Seoul, Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Park
authors.forename: K C
authors.initials: KC
authors.lastname: Kang
authors.forename: K Y
authors.initials: KY
authors.lastname: Kim
authors.forename: P Y
authors.initials: PY
authors.lastname: Jeong
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.forename: D J
authors.initials: DJ
authors.lastname: Adams
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.forename: Y K
authors.initials: YK
authors.lastname: Paik
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001599:Berberine / Q000031:analogs & derivatives / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002687:Chitin Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D013261:Sterols / Q000096:biosynthesis
chemical_list: D000935:Antifungal Agents; D001600:Berberine Alkaloids; C429324:HWY289; D013261:Sterols; D001599:Berberine; C009090:protoberberine; D002687:Chitin Synthase; C400821:chitin synthase 2