The Candida albicans Cdr2p ATP-binding cassette (ABC) transporter confers resistance to caspofungin.
Multidrug resistance may pose a serious problem to antifungal therapy. The Candida albicans Cdr2p is one of two ATP-binding cassette (ABC) transporters mediating antifungal resistance in vivo through increased drug efflux. Echinocandins such as caspofungin represent the newest class of antifungals that target cell wall synthesis. We show here by agar plate resistance assays that cross-resistant clinical isolates of C. albicans display high minimal inhibitory concentrations (MICs) to caspofungin when compared with a sensitive ATCC reference strain. Northern analysis and immunoblotting indicate that these isolates also show high levels of CDR1 and CDR2 expression. To determine a possible contribution of Cdr1p or Cdr2p to caspofungin resistance, we have functionally expressed Cdr1p and Cdr2p in appropriate recipient strains of the yeast Saccharomyces cerevisiae. Yeast cells expressing Cdr1p or Cdr2p exhibit cross-resistance to established antifungal drugs such as azoles and terbinafine. However, Cdr2p and, to a much lesser extent, Cdr1p confer caspofungin hyper-resistance when expressed in yeast. Likewise, Cdr2p confers caspofungin resistance when constitutively overexpressed in a drug-sensitive C. albicans strain. We therefore propose that Cdr2p may contribute to clinical candin resistance. Finally, our data suggest that cross-resistance phenotypes of clinical isolates are the consequence of distinct mechanisms that may operate simultaneously.
Schuetzer-Muehlbauer
Manuela
M
Institute of Medical Biochemistry, Department of Molecular Genetics, University and BioCenter of Vienna, Dr Bohr-Gasse 9/2, A-1030 Vienna, Austria.
Willinger
Birgit
B
Krapf
Gerd
G
Enzinger
Sabine
S
Presterl
Elisabeth
E
Kuchler
Karl
K
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001483:Base Sequence; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism*; D000077336:Caspofungin; D017931:DNA Primers; D004352:Drug Resistance, Microbial / Q000502:physiology*; D054714:Echinocandins; D005656:Fungal Proteins / Q000502:physiology*; D055666:Lipopeptides; D008854:Microscopy, Electron; D010455:Peptides; D010456:Peptides, Cyclic
D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D017931:DNA Primers; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D000077336:Caspofungin