Capisterones A and B, which Enhance Fluconazole Activity in Saccharomyces cerevisiae, from the Marine Green Alga Penicillus capitatus

• Published in: Journal of natural products (Washington, D.C.) Vol. 69; no. 4; pp. 542 - 546
• Main Authors: Li, Xing-Cong, Jacob, Melissa R, Ding, Yuanqing, Agarwal, Ameeta K, Smillie, Troy J, Khan, Shabana I, Nagle, Dale G, Ferreira, Daneel, Clark, Alice M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-04-2006; Glendale, AZ American Society of Pharmacognosy
• Subjects: Antifungal Agents - chemistry; Antifungal Agents - isolation & purification; Antifungal Agents - pharmacology; Ascomycota - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Bahamas; Biological and medical sciences; Candida albicans; Candida albicans - chemistry; Candida albicans - metabolism; Chlorophyta - chemistry; Drug Resistance, Fungal; Drug Screening Assays, Antitumor; Fluconazole - pharmacology; Fungal Proteins - metabolism; General pharmacology; Humans; Lindra; Lindra thallasiae; Marine Biology; Medical sciences; Membrane Transport Proteins - metabolism; Molecular Structure; Penicillus capitatus; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Saccharomyces cerevisiae; Saccharomyces cerevisiae - metabolism; Sterols - chemistry; Sterols - isolation & purification; Sterols - pharmacology; Triterpenes - chemistry; Triterpenes - isolation & purification; Triterpenes - pharmacology; Pentacyclic compound; Steroid; Synergist; Saturated compound; Ketol; Fungi; Marine environment; Antifungal agent; Organic sulfate; Ascomycetes; Inhibition; Acylate; Thallophyta; Terpenoid; Fluconazole; Algae; Cycloartane derivatives; Ketone; In vitro; Biological activity; Resistance; Membrane pump; Chlorophyta; Absolute configuration; Plant origin; Triterpene; Isolation; Saccharomyces cerevisiae; Structural analysis
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np050396y

A whole-cell-based assay using Saccharomyces cerevisiae strains that overexpress Candida albicans CDR1 and MDR1 efflux pumps has been employed to screen natural product extracts for reversal of fluconazole resistance. The tropical green alga Penicillus capitatus was selected for bioassay-guided isolation, leading to the identification of capisterones A and B (1 and 2), which were recently isolated from this alga and shown to possess antifungal activity against the marine pathogen Lindra thallasiae. Current work has assigned their absolute configurations using electronic circular dichroism and determined their preferred conformations in solution based on detailed NOE analysis. Compounds 1 and 2 significantly enhanced fluconazole activity in S. cerevisiae, but did not show inherent antifungal activity when tested against several opportunistic pathogens or cytotoxicity to several human cancer and noncancerous cell lines (up to 35 μM). These compounds may have a potential for combination therapy of fungal infections caused by clinically relevant azole-resistant strains.