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Antimicrobial Agents and Chemotherapy, February 2009, p. 354-369, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01095-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Abc1p Is a Multidrug Efflux Transporter That Tips the Balance in Favor of Innate Azole Resistance in Candida krusei{triangledown}

Erwin Lamping,1* Amrita Ranchod,1 Kenjirou Nakamura,2 Joel D. A. Tyndall,3 Kyoko Niimi,1 Ann R. Holmes,1 Masakazu Niimi,4 and Richard D. Cannon1

Department of Oral Sciences, University of Otago, Dunedin, New Zealand,1 Advanced Research Center, Nippon Dental University, School of Life Dentistry, Niigata, Japan,2 National School of Pharmacy, University of Otago, Dunedin, New Zealand,3 Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan4

Received 14 August 2008/ Returned for modification 16 October 2008/ Accepted 8 November 2008

Most Candida 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, of C. 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 investigate ERG11 and ABC1 expression in C. krusei. Examination of the ERG11 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 distinct ERG11 alleles in one of two C. krusei strains. Functional overexpression of ERG11 and ABC1 in Saccharomyces cerevisiae conferred high levels of resistance to azoles and a range of unrelated Abc1p pump substrates, while small molecule inhibitors of Abc1p chemosensitized C. krusei to azole antifungals. Our data show that despite the presence of multiple alleles of ERG11 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 of C. krusei.

* Corresponding author. Mailing address: Department of Oral Sciences, University of Otago, P.O. Box 647, Dunedin 9054, New Zealand. Phone: 64 3 479 7435. Fax: 64 3 479 7078. E-mail: erwin.lamping{at}otago.ac.nz

{triangledown} Published ahead of print on 17 November 2008.

Antimicrobial Agents and Chemotherapy, February 2009, p. 354-369, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01095-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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