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

Kang Sik Park, Kap Chul Kang, Ki Young Kim, Pan Young Jeong, Jai Hyun Kim, David J. Adams, Jung Ho Kim, Young Ki Paik

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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-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.

Original languageEnglish
Pages (from-to)513-519
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume47
Issue number5
DOIs
Publication statusPublished - 2001 Jan 1

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All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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