Studies for the Elucidation of the Mode of Action of the Antimycotic Hydroxypyridone Compound, Rilopirox

Kruse, Regina; Hengstenberg, Wolfgang; Hänel, H.; Raether, W.

doi:10.1159/000138852

Cited by 12 publications

(6 citation statements)

References 10 publications

(13 reference statements)

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“…Mimosine has been extensively studied in Australian sheep as a defleecing agent [62]. Ciclopirox, which as predicted [8] inhibits deoxyhypusyl hydroxylation, is widely employed clinically as an excellent topical fungicide [63], its analog piroctone is a cosmetically applied anti-dandruff agent [64], and the analog rilopirox under investigation as an antimycotic [65,66]. AbeAdo, studied for its potential as an antiparasitic and antineoplastic compound, was proposed to exert its antiproliferative effect by depletion of elF-5A [67,68].…”

Section: Resultsmentioning

confidence: 99%

Detection of a sub‐set of polysomal mRNAs associated with modulation of hypusine formation at the G1‐S boundary Proposal of a role for eIF‐5A in onset of DNA replication

et al. 1995

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S phase entry, I.e. start of DNA replication, Is a crucial step in proliferation. Inhibition of S phase entry correlates with Inbibition of hypusine formation, an event affecting only the eukaryotie Initiation factor $A (elF4A), Its hypuslnecontalning sequence wus postulated to authorize polysomal utilization of specific trauscripts for proteins necessary to enable DNA replication. Using ndmodne to reversibly suppress the hyposinc-forming deoxyhypusyi hydmxylase (E.C. 1.1¢99.29) in cells while differentially displaying their polysomal versus non-polysemal mRNA popolations, we report the detection and cla~!fleation of several mRNA species that indeed disappear from and reappear at !lo1-ysomes in con~rt with inhibition and d_!s!nhibition, respectively, of hypusine formation. Based on initial sequence data, two trauslationally controlled enzymes, both critical for proliferation, are identified us candicate wodncts of such mRNAs, methionine adenosyitrausferuse (E.C 2.$.1.6) and cytochrome-c oxiduse 0gC 1.9.3.1) subunit 1. The existence of such potative hyposinedependent messenger nnclde adds (/O, mas) prevides the basis for a proposal on their molecular function in onset of multiplication.Key words: Post-translational modification; eIF-5A; Hypusine; Cell cycle control; Translational control; mRNA I, IntroductionThe unique amino acid hypusine [~-(4-amino-2(R).hydroxybutyl)-t.-lysine] is formed post-translationally by the sequential action of deoxyhypusyl synthase (DOHS) and deoxyhypusyl hydroxylase (DOHH) on a single lysyl residue in only one cellular protein, the eukaryotic initiation factor 5A (elF-SA) [I-3]. The hypusine-containing domain shows remarkable interspecies conservation, and a sequence of 12 amino acids containing the hypusine residue has been strictly conserved throughout eukaryotic evolution, from fungi to plants, insects, and mammals [3]. Hypusine formation, which has not been demonstrated in prokaryotes [2], is an absolute requirement for growth of $. cerevesiae [4], and a number of *Correspondin8 authors, Fax: (I) (212) 746 0300 and Fax: (I) (212) 746 6382, respectively.'For Stephen Biko (December 18, 1944.-September 12, 1977.reports have established correlations between hypusine formation and the proliferation of eukaryotic cells (see [2,3]). However, the exact physiological function of this presumed translation initiatic~n factor is unknown, and at present it even is unclear whether elF-SA functions at the pretranslational and/ or the translational level [3].Deoxyhypusyl hydroxylase (E.C. 1.14.99.29), which catalyses the final step of hypusine biosynthesis, is apparently related [5,6] to other protein hydroxy]ating enzymes such as prolyl 4-hydroxylase (E.C 1.14.11.2) [7] and is effectively inhibited by mimosine (3-(N-(3-hydroxypyridin-4-one))-2[S]-aminopropionic acid), both in vitro and in culture [3]. This coincides with proliferative arrest in the late GI phase ofthe cell cycle [3,[8][9][10][11]. Fast recovery ofcellular DOHH activity occurs upon mimo,,;ine removal, an effect parallele...

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Section: Resultsmentioning

confidence: 99%

Detection of a sub‐set of polysomal mRNAs associated with modulation of hypusine formation at the G1‐S boundary Proposal of a role for eIF‐5A in onset of DNA replication

et al. 1995

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“…For rilopirox, a high affinity for iron ions has been shown in complexometric studies (37). Furthermore, rilopirox inhibited the activity of a catalase from Aspergillus niger and the respiratory chain in mitochondria and submitochondrial particles in Saccharomyces cerevisiae (37). Since both catalases and enzymes of the respiratory chain are iron-dependent proteins, this further supported the view that iron binding may play a major role in the mode of action of hydroxypyridone antimycotics.…”

mentioning

confidence: 80%

“…Therefore, it was hypothesized that the chelation of metal ions and the inhibition of iron-dependent enzymes play a primary role in the action of ciclopirox olamine (1). For rilopirox, a high affinity for iron ions has been shown in complexometric studies (37). Furthermore, rilopirox inhibited the activity of a catalase from Aspergillus niger and the respiratory chain in mitochondria and submitochondrial particles in Saccharomyces cerevisiae (37).…”

mentioning

confidence: 99%

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

Niewerth

Kunze

Seibold

et al. 2003

Antimicrob Agents Chemother

129

128

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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...

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“…The present findings are in agreement with previous data obtained with C. albicans [22] and now extend our knowledge to C. tropicalis and C. glabrata, and compare it with nystatin and fluconazole. The proposed mechanism of action for rilopi rox (hydroxypyridone) is that this compound forms complexes with iron cations which are essential for fungal cells [24], and already after the 1st h of contact with 1 MIC rilopirox the surface of Candida cells had become rough and folds and flat cells had appeared [25]. Nystatin (polyene) acts by binding to ergosterol and other sterol groups thus al tering membrane functions [26], and this in teraction leads also to a decrease in hydrophobicity of the fungi with a parallel reduction in adherence [27], Fluconazole (triazole) acts on ergosterol synthesis, and inhibition of the syn thesis of ergosterol has a number of effects that influence the activity of membranebound enzymes and interfere with cell archi tecture [28].…”

Section: R Esu Ltsmentioning

confidence: 99%

Experimental Evidences for a Role of Subinhibitory Concentrations of Rilopirox, Nystatin and Fluconazole on Adherence of <i>Candida</i> spp. to Vaginal Epithelial Cells

et al. 1996

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Candidiasis is frequently localized in the mucosal epithelium which covers the vaginal and oral cavity. The pathogenicity of Candida is correlated with its ability to adhere to epithelial cells and this is the resultant of both fungal and host cell properties and their physicochemical interactions. This study was performed to investigate the ability of subinhibitory concentrations (sub-MICs) of rilopirox, a new antimycotic drug, to interfere with the adhesion of Candida albicans, Candida tropicalis and Candida glabrata to human vaginal cells, in comparison with sub-MICs of nystatin and fluconazole. The three drugs are more active on C albicans, followed by C. tropicalis and, last, C glabrata, on which fluconazole was inactive (MIC > 24 μg/ml). Rilopirox, nystatin and fluconazole have different mechanisms of action, and different molecular weights, so a comparative analysis of data was performed by means of their sub-MICs. On this basis the order of activity was nystatin = rilopirox > fluconazole. These findings can be of use for optimizing also the posologic design by regarding sub-MICs which are still active in reducing the adhesiveness of Candida to cells of the vaginal mucosa.

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Studies for the Elucidation of the Mode of Action of the Antimycotic Hydroxypyridone Compound, Rilopirox

Cited by 12 publications

References 10 publications

Detection of a sub‐set of polysomal mRNAs associated with modulation of hypusine formation at the G1‐S boundary Proposal of a role for eIF‐5A in onset of DNA replication

Detection of a sub‐set of polysomal mRNAs associated with modulation of hypusine formation at the G1‐S boundary Proposal of a role for eIF‐5A in onset of DNA replication

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

Experimental Evidences for a Role of Subinhibitory Concentrations of Rilopirox, Nystatin and Fluconazole on Adherence of <i>Candida</i> spp. to Vaginal Epithelial Cells

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