RÉSUMÉ
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 microM). These compounds may have a potential for combination therapy of fungal infections caused by clinically relevant azole-resistant strains.
Sujet(s)
Antifongiques , Chlorophyta/composition chimique , Fluconazole/pharmacologie , Saccharomyces cerevisiae/métabolisme , Stérols , Triterpènes , Glycoprotéine P/métabolisme , Antifongiques/composition chimique , Antifongiques/isolement et purification , Antifongiques/pharmacologie , Ascomycota/effets des médicaments et des substances chimiques , Bahamas , Candida albicans/composition chimique , Candida albicans/métabolisme , Résistance des champignons aux médicaments , Tests de criblage d'agents antitumoraux , Protéines fongiques/métabolisme , Humains , Biologie marine , Protéines de transport membranaire/métabolisme , Structure moléculaire , Stérols/composition chimique , Stérols/isolement et purification , Stérols/pharmacologie , Triterpènes/composition chimique , Triterpènes/isolement et purification , Triterpènes/pharmacologieRÉSUMÉ
Antifungal bioassay-guided isolation of the ethanol extract of the roots of Pentagonia gigantifolia yielded 6-octadecynoic acid (1) and the new 6-nonadecynoic acid (2). Compounds 1 and 2 inhibited the growth of fluconazole-susceptible and -resistant Candida albicans strains. Their antifungal potencies were comparable to those of amphotericin B and fluconazole. Of particular significance is the low cytotoxicity and specific activity of 1 and 2 against C. albicans.