Genome-wide expression profiling of the response to ciclopirox olamine in Candida albicans
Robin E B Lee1, Teresa T Liu, Katherine S Barker
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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.
Insights
Ciclopirox olamine, an anti-infective agent, alters gene expression in Candida albicans, particularly affecting iron uptake genes. Multidrug efflux pump genes CDR1 and CDR2 do not influence susceptibility to this agent.
Area of Science:
- Mycology
- Molecular Biology
- Pharmacology
Background:
- Candida albicans is a common fungal pathogen.
- Understanding the mechanism of action of anti-infective agents is crucial for developing new treatments.
- Ciclopirox olamine is a hydroxypyridone derivative with anti-infective properties.
Purpose of the Study:
- To investigate the gene expression profile changes in Candida albicans when exposed to ciclopirox olamine.
- To elucidate the mechanism of action of ciclopirox olamine.
Main Methods:
- Candida albicans SC5314 was treated with ciclopirox olamine at IC50 concentration for 3 hours.
- Gene expression profiles were analyzed using DNA microarrays.
- Differential gene expression was confirmed by real-time RT-PCR.
- Susceptibility of various gene-disrupted mutants to ciclopirox olamine was assessed.
Main Results:
- Exposure to ciclopirox olamine resulted in differential expression of 49 genes in Candida albicans.
- Upregulated and downregulated genes were involved in small molecule transport, iron uptake, and cell stress.
- Genes related to iron uptake showed significant changes in expression.
- Mutations in CDR2, or both CDR1 and CDR2, and overexpression of CDR1/CDR2 did not alter susceptibility to ciclopirox olamine.
Conclusions:
- Ciclopirox olamine's mechanism of action is consistent with iron chelation, as evidenced by induced changes in iron uptake gene expression.
- The multidrug efflux pump genes CDR1 and CDR2 are induced by ciclopirox olamine but do not play a role in the susceptibility to this antifungal agent.
