Open AccessAbc1p Is a Multidrug Efflux Transporter That Tips the Balance in Favor of Innate Azole Resistance in Candida krusei
Author(s) -
Erwin Lamping,
Amrita Ranchod,
K. Nakamura,
Joel D. A. Tyndall,
Kyoko Niimi,
Ann R. Holmes,
Masakazu Niimi,
Richard D. Can
Publication year - 2009
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01095-08
Subject(s) - candida krusei , efflux , microbiology and biotechnology , fluconazole , biology , azole , multiple drug resistance , drug resistance , genetics , antifungal
MostCandida krusei strains are innately resistant to fluconazole (FLC) and can cause breakthrough candidemia in immunocompromised individuals receiving long-term prophylactic FLC treatment. Although the azole drug target, Erg11p, ofC. krusei has a relatively low affinity for FLC, drug efflux pumps are also believed to be involved in its innate FLC resistance. We describe here the isolation and characterization of Abc1p, a constitutively expressed multidrug efflux pump, and investigateERG11 andABC1 expression inC. krusei . Examination of theERG11 promoter revealed a conserved azole responsive element that has been shown to be necessary for the transcription factor Upc2p mediated upregulation by azoles in related yeast. Extensive cloning and sequencing identified three distinctERG11 alleles in one of twoC. krusei strains. Functional overexpression ofERG11 andABC1 inSaccharomyces cerevisiae conferred high levels of resistance to azoles and a range of unrelated Abc1p pump substrates, while small molecule inhibitors of Abc1p chemosensitizedC. krusei to azole antifungals. Our data show that despite the presence of multiple alleles ofERG11 in some, likely aneuploid,C. krusei strains, it is mainly the low affinity of Erg11p for FLC, together with the constitutive but low level of expression of the multidrug efflux pump Abc1p, that are responsible for the innate FLC resistance ofC. krusei .