Reversal of fluconazole resistance by sulfated sterols from the marine sponge Topsentia sp.
Bioassay-guided fractionation of the extract of Topsentia sp. led to the identification of two new sulfated sterols, geodisterol-3-O-sulfite (1) and 29-demethylgeodisterol-3-O-sulfite (2), the active constituents reversing efflux pump-mediated fluconazole resistance. Both compounds enhanced the activity of fluconazole in a Saccharomyces cerevisiae strain overexpressing the Candida albicans efflux pump MDR1, as well as in a fluconazole-resistant Candida albicans clinical isolate known to overexpress MDR1. These results provide insight into the clinical utility of combining efflux pump inhibitors with current antifungals to combat the resistance associated with opportunistic fungal infections caused by C. albicans.
Digirolamo
Jessica A
JA
Department of Pharmacognosy, National Center for Natural Products Research, and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
Li
Xing-Cong
XC
Jacob
Melissa R
MR
Clark
Alice M
AM
Ferreira
Daneel
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D019450:Genes, MDR / Q000187:drug effects; D008386:Marine Biology; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013261:Sterols / Q000737:chemistry / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013463:Sulfuric Acid Esters / Q000737:chemistry / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D013261:Sterols; D013463:Sulfuric Acid Esters; D015725:Fluconazole