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...

Background:In contrast to the increasing numbers of agents for the treatment of invasive fungal infections, discoveries of new antifungal agents with therapeutic value in dermatomycoses are reported only rarely. Methods: Abafungin (chemical abstracts service registry No. 129639-79/8) is the first member of a novel class of synthetic antifungal compounds, the arylguanidines. It was first synthesized at Bayer AG, Leverkusen, Germany, and its antifungal action was discovered during the screening of H₂-receptor antagonists based on the structure of famotidine. To obtain insight into its mode of action and antifungal activity, various tests were carried out with different fungal pathogensin vitro. Results: Abafungin was found to have potent antifungal activity. Furthermore, mode-of-action studies suggested that abafungin exerts its antifungal activity regardless of whether the pathogens are growing or in a resting state. One target of abafungin was found to be the inhibition of transmethylation at the C-24 position of the sterol side chain, catalyzed by the enzyme sterol-C-24-methyltransferase. A second action of abafungin seems to be a direct effect on the fungal cell membrane.Conclusion: The observed characteristics of abafungin indicate that abafungin might be a promising antifungal agent defining a new class of antimycotics.

Onychomycoses, infections of the nail caused by fungi, are amongst the most common illnesses. Because of the high incidence of these infections and problems involved in their therapy, they have received much attention, particularly as concerns a better characterisation of the causative micro-organisms. Onychomycosis caused by dermatophytes (tinea unguium) is most common and is found more frequently on the feet than on the hands. The clinical presentation of onychomycosis is at best indicative of fungal infection, and the growth of a credible pathogen is an indispensable prerequisite for definite diagnosis. The clinical appearance is variable. Four major types of manifestation have been characterised, depending on localisation and spread. New antifungal agents for systemic or topical application based on novel active substances or vehicles are available, and cure is feasible for the majority of cases. Therapy can and should be individualised, depending on the characteristics of the particular case. Currently, continuous or intermittent oral treatment with itraconazole or terbinafine exhibit a particularly favourable risk : benefit ratio. Fluconazole might become an alternative in the near future. With respect to topical treatment, ciclopirox or amorolfine lacquer and the bifonazole/urea combination deserve particular interest. However, cure cannot be expected for every case.

These data indicate that metabolic activity, oxygen accessibility and iron levels are critical parameters in the mode of action of ciclopirox olamine.

No abstract

Fifty dermatophyte strains, recently obtained from clinical material, belonging to 4 different species were examined for their susceptibility to 5 systemic or topical antimycotic agents using both an agar macrodilution and a broth microdilution test. Antimycotics compared were griseofulvin, itraconazole, sertaconazole, terbinafine and ciclopiroxolamine. A comparison of the minimum inhibitory concentrations (MIC) clearly showed differences between the two test methods applied. For all 5 antimycotics, MIC data were three- to seventyfold lower in the microdilution test system. These differences, depending on the test method, have to be taken into account when comparing MIC data in the literature or when relating the in vitro data to the tissue concentrations determined in vivo.

Infections due to Candida albicans are frequent and of clinical importance. Especially at a time of increasing organ transplantations, HIV infections, and resistance to antimicrobial agents a profound knowledge of the interaction between C. albicans and host tissue is mandatory. In addition to secreted aspartyl proteinase, dimorphism, cell surface composition, and toxin production phospholipases are a main factor in pathogenicity. Up to the present, many different groups and subgroups of phospholipases have been detected. These different enzymes are related to various types of aggressive and defensive actions. These range from active invasion of host cell tissue to growth control and remodelling of the yeast cell membrane. It is clear that a multiplicity of factors must co-operate to overcome the host's defences. Yet it can be supposed today that phospholipases are one important factor in this complex interaction. Therefore the known phospholipases of C. albicans are described in detail under clinical aspects.

The inhibitory effect of human immunodeficiency virus (HIV) proteinase inhibitors amprenavir and saquinavir and antifungal agents terbinafine, ketoconazole, amphotericin B and ciclopiroxolamine on aspartyl proteinases (Saps) secreted by Candida albicans was tested in an in vitro spectophotometric assay. As expected, both HIV proteinase inhibitors showed a significant inhibitory effect on Sap activity, which was comparable to that of the classical aspartyl proteinase inhibitor pepstatin A (P < 0.001). Antifungal drugs such as ketoconazole, terbinafine and amphotericin B had no, or only minor, inhibitory effects on proteolytic activity. In contrast, a significant reduction in Sap activity could be demonstrated during treatment with the antifungal agent ciclopiroxolamine (P < 0.001). These results point to a multiple effect of this antimycotic agent and might explain the reduced adherence of C. albicans to human epithelial cells at subinhibitory doses.