Ciclopirox Olamine Treatment Affects the Expression Pattern ofCandida albicansGenes Encoding Virulence Factors, Iron Metabolism Proteins, and Drug Resistance Factors

Abstract

The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examined the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concentration (0.6 g/ml) of ciclopirox olamine by reverse transcription-PCR. In addition, we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up-or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addition of FeCl 3 to ciclopirox olamine-treated cells reversed the effect of the drug. Addition of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While seruminduced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-containing gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be observed even after an incubation period of 6 months. This was in contrast to control experiments with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 months. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.The dimorphic opportunistic fungus Candida albicans is a major cause of mucosal and invasive mycoses. Infections caused by C. albicans are frequently treated with fluconazole, other azole antimycotics, or nonazole antimycotics. The modes of action of the majority of these drugs are well known (24). The imidazoles and triazoles like clotrimazole, ketoconazole, itraconazole, miconazole, fluconazole, and a whole range of similar components act by inhibiting C 14 -demethylase, an enzyme which is involved in the conversion of lanosterol to ergosterol in the ergosterol b...

Expression profiling analysis of hypoxic pulmonary disease

“…Ciclopirox olamine is a synthetic antifungal agent for topical dermatologic treatment of superficial mycoses. It is most useful against tinea versicolor (Niewerth et al, 2003). Antimycotic ciclopirox olamine also acts as a bidentate iron chelator capable of stabilizing HIF-1α and then activating endogenous HIF-1 target genes, including VEGF to promote angiogenesis remodeling (Linden et al, 2003).…”

Candida albicansCell Wall Proteins

“…The stress associated with drug treatment appears not to affect the expression of PLB1. There was no effect of treatment with ciclopirox olamine or fluconazole (RT-PCR [272]), caspofungin (RT-PCR, transcriptional profiling [210,272]), or amphotericin B, ketoconazole, and flucytosine (transcriptional profiling [210]). However, a bisquaternary ammonium salt whose likely target is phospholipase inhibits growth (269).…”

“…Expression is not affected by exposure to ciclopirox olamine or fluconazole (Northern analysis [272]). …”

Development of a Kinetic Spectrophotometry Method for the Determination of Ciclopirox Olamine in Pharmaceutical Sample

“…Studies with human skin of corpses showed capillar penetration through the epidermis to the hair follicles and sebaceous glands, while a portion of the drug remains in the stratum corneum 4 and it presents systemic absorption when applied in cream 1% (CXO). The mechanism of action is related to its chelating action on polyvalent metal cations such as Fe (III) and Al (III) essential for two fungus enzymes, catalase and peroxidase 2,5 . The USP has published two standard methods for the determination of CXO in pharmaceutical formulations, by HPLC 6 and spectrophotometry 7 .…”