This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Lamping, E. Articles by Cannon, R. D. PubMed PubMed Citation Articles by Lamping, E. Articles by Cannon, R. D.

 Previous Article  |  Next Article 

Antimicrob. Agents Chemother. doi:10.1128/AAC.01095-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Abc1p is a multidrug efflux transporter that tips the balance in favour of innate azole resistance in Candida krusei

Department of Oral Sciences, University of Otago, Dunedin, New Zealand; Graduate School of Life Dentistry, Nippon Dental University, Niigata, Japan; National School of Pharmacy, University of Otago, Dunedin, New Zealand; Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan

^* To whom correspondence should be addressed. Email: erwin.lamping{at}otago.ac.nz.

	Abstract

Most Candida krusei strains are innately resistant to fluconazole (FLC) and can cause breakthrough candidemias 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. This paper describes the isolation and characterization of Abc1p, a constitutively expressed multidrug efflux pump, and investigates ERG11 and ABC1 expression in C. krusei. Examination of the ERG11 promoter revealed a conserved azole responsive element (ARE) 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 over-expression of ERG11 and ABC1 in S. 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.