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

• Published in: Journal of antimicrobial chemotherapy Vol. 55; no. 5; pp. 655 - 662
• Main Authors: Lee, Robin E. B., Liu, Teresa T., Barker, Katherine S., Lee, Richard E., Rogers, P. David
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-05-2005; Oxford Publishing Limited (England)
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; antifungal activity; Antifungal Agents - pharmacology; Biological and medical sciences; C. albicans; Candida albicans; Candida albicans - drug effects; Candida albicans - genetics; Candida albicans - growth & development; Candida albicans - metabolism; efflux pumps; Fungal Proteins - genetics; Fungal Proteins - metabolism; Gene Expression Profiling; Gene Expression Regulation, Fungal; gene regulation; Genome, Fungal; Humans; Medical sciences; microarrays; Microbial Sensitivity Tests; Mutation; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Pyridones - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Candida albicans; Yeast; Ciclopirox; antifungal activity; microarrays; Fungi; Antifungal agent; Regulation(control); Gene; C. albicans; gene regulation; Olamine; Fungi Imperfecti; Genome; efflux pumps; Thallophyta
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dki105

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.