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JAC Advance Access published online on April 6, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki105
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received November 19, 2004
Revised February 21, 2005
Accepted February 25, 2005

Original article

Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans

Robin E. B. Lee 1, Teresa T. Liu 2, Katherine S. Barker 2, Richard E. Lee 3, and P. David Rogers 4*

1 Departments of Pharmaceutical Sciences, USA and
2 Departments of Pharmacy, College of Pharmacy, USA; Children's Foundation Research Center at Le Bonheur Children's Medical Center, Memphis, TN 38103, USA
3 Departments of Pharmaceutical Sciences, USA
4 Departments of Pharmaceutical Sciences, USA; Departments of Pharmacy, College of Pharmacy, USA; Children's Foundation Research Center at Le Bonheur Children's Medical Center, Memphis, TN 38103, USA; Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA

* To whom correspondence should be addressed.
P. David Rogers, E-mail: drogers{at}utmem.edu


  Abstract

Objectives: The aim of this study was to identify changes in the gene expression profile of Candida albicans upon exposure to the hydroxypyridone anti-infective agent ciclopirox olamine in an effort to better understand its mechanism of action.

Methods: C. albicans SC5314 was exposed to either medium alone or ciclopirox olamine at a concentration equivalent to the IC50 (0.24 mg/L) for 3 h. RNA was isolated and gene expression profiles were compared using DNA microarrays. Differential expression of select genes was confirmed by real-time reverse transcription (RT)-PCR. Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clinical isolate overexpressing CDR1 and CDR2, were examined for changes in susceptibility to ciclopirox olamine.

Results: A total of 49 genes were found to be responsive to ciclopirox olamine, including 36 up-regulated genes and 13 down-regulated genes. These included genes involved in small molecule transport (HGT11, HXT5, ENA22, PHO84, CDR4), iron uptake (FRE30, FET34, FTR1, FTR2, SIT1) and cell stress (SOD1, SOD22, CDR1, DDR48). Mutants disrupted for CDR2 and both CDR1 and CDR2, as well as a clinical isolate overexpressing CDR1 and CDR2, showed no change in susceptibility to ciclopirox olamine compared with the respective parent.

Conclusions: Consistent with the hypothesis that ciclopirox olamine acts as an iron chelator, it induced changes in expression of many genes involved in iron uptake. Despite induction of the multidrug efflux pump genes CDR1 and, to a lesser extent, CDR2 by ciclopirox olamine, these genes do not affect susceptibility to this agent.

Keywords: microarrays; gene regulation; C. albicans; antifungal activity; efflux pumps.
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