Capisterones A and B, which enhance fluconazole activity in Saccharomyces cerevisiae, from the marine green alga Penicillus capitatus.
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.
Li
Xing-Cong
XC
National Center for Natural Products Research and Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. xcli@olemiss.edu
Jacob
Melissa R
MR
Ding
Yuanqing
Y
Agarwal
Ameeta K
AK
Smillie
Troy J
TJ
Khan
Shabana I
SI
Nagle
Dale G
DG
Ferreira
Daneel
D
Clark
Alice M
AM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001203:Ascomycota / Q000187:drug effects; D001444:Bahamas; D002176:Candida albicans / Q000737:chemistry / Q000378:metabolism; D000460:Chlorophyta / Q000737:chemistry*; D025141:Drug Resistance, Fungal; D004354:Drug Screening Assays, Antitumor; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000378:metabolism; D006801:Humans; D008386:Marine Biology; D026901:Membrane Transport Proteins / Q000378:metabolism; D015394:Molecular Structure; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D013261:Sterols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D013261:Sterols; D014315:Triterpenes; C510701:capisterone A; C510702:capisterone B; D015725:Fluconazole